Roberto Collu

Special AT-rich sequence-binding protein 2 (SATB2) is a master regulator of gene expression. Mutations of the SATB2 gene results in the SATB2-associated syndrome (SAS), a genetic disorder characterized by neurodevelopmental disabilities and autism-related phenotype. The importance of plasma as an indicator of SAS phenotypes is unknown. We aim to investigate if pathogenic variants in SATB2 are associated with alteration to relevant pathways in the plasma of SAS patients and identify key differentially regulated proteins which may serve as biomarkers to improve diagnostic and future pharmacological approaches. We used well-validated proteomic technologies to determine the proteomic profile of plasma from SAS patients compared to healthy control subjects. Bioinformatical analysis was performed to identify significant proteins and functionally enriched pathways. We identified differentially expressed proteins in the plasma of SAS patients that are significantly involved in metabolism-related pathways. Energy metabolism, glucose metabolism and vitamin metabolism pathways are significantly enriched in SAS patients as compared to healthy controls. Our study linked SATB2 mutations to the impairment of plasma proteins involved in different metabolic pathways in SAS patients.

Identifying phenotypes at high risk of suicidal behaviour is a relevant objective of clinical and translational research and can facilitate the identification of possible candidate biomarkers. We probed the potential association and eventual stability of neuropsychological profiles and serum BDNF concentrations with lifetime suicide ideation and attempts (LSI and LSA, respectively) in individuals with schizophrenia (SCZ) and schizoaffective disorder (SCA) in a 2-year follow-up study. A secondary analysis was conducted on a convenience sample of previously recruited subjects from a single outpatient clinic. Retrospectively assessed LSI and LSA were recorded by analysing the available longitudinal clinical health records. LSI + LSA subjects consistently exhibited lower PANSS-defined negative symptoms and better performance in the BACS-letter fluency subtask. There was no significant association between BDNF levels and either LSI or LSA. We found a relatively stable pattern of lower negative symptoms over two years among patients with LSI and LSA. No significant difference in serum BDNF concentrations was detected. The translational viability of using neuropsychological profiles as a possible avenue for the identification of populations at risk for suicide behaviours rather than the categorical diagnosis represents a promising option but requires further confirmation.

Schizophrenia (SCZ) and schizoaffective disorder (SAD) are severe and complex psychiatric disorders whose liability threshold is modulated by the interplay of biological, mainly genetic, and environmental factors. Consistent evidence has pointed to the role of serum brain‐derived neurotrophic factor (BDNF) as a plausible illness biomarker in SCZ spectrum disorders. There is no consensus, however, on the temporal trajectory of this decline. Here, we present a secondary analysis of the Longitudinal Assessment of BDNF in Sardinian Psychotic patients (LABSP) study, focusing on the impact of antipsychotic therapy, particularly long‐acting injectable (LAI), on the longitudinal trajectory of serum BDNF levels and analyzing the effect of BDNF genetic variants. LABSP patients were assessed every 6 months for a series of measures, including the assessment of BDNF serum levels over 24 months. Blood samples for each patient were taken at the same time of the day (between 8:00 and 10:00 a.m.). BDNF serum levels were determined using the BDNF ELISA Kit. Four tag single nucleotide polymorphisms (SNPs) within the BDNF gene (rs1519480, rs11030104, rs6265 [Val66Met], and rs7934165) were selected using standard parameters and analyzed with polymerase chain reaction (PCR). Mixed‐effects linear regression models (MLRMs) were used to analyze longitudinal data. Twenty‐four patients out of 105 LABSP (22.9%) patients received therapy with LAI. Analysis with MLRM showed a significant effect of LAI treatment associated with increasing serum BDNF levels (Z = 2.2, p = 0.02). However, oral antipsychotics did not significantly impact the longitudinal trajectory of serum BDNF levels (Z = 0.15, p = 0.9). There was no moderating effect of variants within the BDNF gene on the identified association. We identified a significant longitudinal increase in serum BDNF in SCZ and SAD patients treated with LAI antipsychotic therapy. The significant impact of this preparation of antipsychotic treatment on serum BDNF, despite the limited sample size, points to a moderate to large magnitude of effect that should be investigated in future prospective studies.

Brain-derived neurotrophic factor (BDNF) is a key modulator of neuroplasticity and has an important role in determining the susceptibility to severe psychiatric disorder with a significant neurodevelopmental component such as major psychoses. Indeed, a potential association between BDNF serum levels and schizophrenia (SCZ) and schizoaffective disorder (SAD) has been tested in diverse studies and a considerable amount of them found reduced BDNF levels in these disorders. Here, we aimed at testing the association of BDNF serum levels with several demographic, clinical, and psychometric measures in 105 patients with SCZ and SAD, assessing the moderating effect of genetic variants within the BDNF gene. We also verified whether peripheral BDNF levels differed between patients with SCZ and SAD. Our findings revealed that BDNF serum levels are significantly lower in patients affected by SCZ and SAD presenting more severe depressive symptomatology. This finding awaits replication in future independent studies and points to BDNF as a possible prognostic indicator in major psychoses.

Background and hypothesis: Schizophrenia spectrum disorders are among the most debilitating mental disorders and has complex pathophysiological underpinnings. There is growing evidence that brain-derived neurotrophic factor (BDNF) can play a role in its pathogenesis. The present study investigated the longitudinal variation of serum BDNF levels in a 24-month observational prospective cohort study of Sardinian psychotic patients and its relationship with psychopathological and cognitive changes. Furthermore, we examined whether genetic variation within theBDNFgene could moderate these relationships.Study design: Every 6 months, 105 patients were assessed for their BDNF serum levels, as well as for a series of psychopathological, cognitive, and social measures. We performed a targeted analysis of four tag single nucleotide polymorphisms within theBDNFgene that were selected and analyzed using polymerase chain reaction. Longitudinal data were analyzed using mixed-effects linear regression models.Study results: We observed a declining longitudinal trajectory of BDNF levels in psychotic patients in general, and in relation to the severity of depressive and negative symptoms. BDNF serum levels also declined in patients scoring lower in cognitive measures such as attention and speed of information processing and verbal fluency. The rs7934165 polymorphism moderated the significant association between verbal fluency and BDNF levels.Conclusions: These findings in patients from real-world settings suggest a plausible role of peripheral BDNF levels as a marker of illness burden in schizophrenia spectrum disorders.

Objective: Despite the growing knowledge on the functional relationship between an altered endocannabinoid (eCB) system and development of anorexia nervosa (AN), to date no studies have investigated the central eCB tone in the activity‐based anorexia (ABA) model that reproduces key aspects of human AN.Method: We measured levels of two major eCBs, anandamide (AEA) and 2‐arachidonoylglycerol (2‐AG), those of two eCB‐related lipids, oleoylethanolamide (OEA) and palmitoylethanolamide (PEA), and the cannabinoid type‐1 receptor (CB1R) density in the brain of female ABA rats, focusing on areas involved in homeostatic and rewarding‐related regulation of feeding behavior (i.e., prefrontal cortex, nucleus accumbens, caudato putamen, amygdala, hippocampus and hypothalamus). Analysis was carried out also at the end of recovery from the ABA condition.Results: At the end of the ABA induction phase, 2‐AG was significantly decreased in ABA rats in different brain areas but not in the caudato putamen. No changes were detected in AEA levels in any region, whereas the levels of OEA and PEA were decreased exclusively in the hippocampus and hypothalamus. Furthermore, CB1R density was decreased in the dentate gyrus of hippocampus and in the lateral hypothalamus. After recovery, both 2‐AG levels and CB1R density were partially normalized in some areas. In contrast, AEA levels became markedly reduced in all the analyzed areas.Discussion: These data demonstrate an altered brain eCB tone in ABA rats, further supporting the involvement of an impaired eCB system in AN pathophysiology that may contribute to the maintenance of some symptomatic aspects of the disease.