Role of PATJ in stroke prognosis by modulating endothelial to mesenchymal transition through the Hippo/Notch/PI3K axis.

Through GWAS studies we identified PATJ associated with functional outcome after ischemic stroke (IS). The aim of this study was to determine PATJ role in brain endothelial cells (ECs) in the context of stroke outcome. PATJ expression analyses in patient's blood revealed that: (i) the risk allele of rs76221407 induces higher expression of PATJ, (ii) PATJ is downregulated 24 h after IS, and (iii) its expression is significantly lower in those patients with functional independence, measured at 3 months with the modified Rankin scale ((mRS) ≤2), compared to those patients with marked disability (mRS = 4-5). In mice brains, PATJ was also downregulated in the injured hemisphere at 48 h after ischemia. Oxygen-glucose deprivation and hypoxia-dependent of Hypoxia Inducible Factor-1α also caused PATJ depletion in ECs. To study the effects of PATJ downregulation, we generated PATJ-knockdown human microvascular ECs. Their transcriptomic profile evidenced a complex cell reprogramming involving Notch, TGF-ß, PI3K/Akt, and Hippo signaling that translates in morphological and functional changes compatible with endothelial to mesenchymal transition (EndMT). PATJ depletion caused loss of cell-cell adhesion, upregulation of metalloproteases, actin cytoskeleton remodeling, cytoplasmic accumulation of the signal transducer C-terminal transmembrane Mucin 1 (MUC1-C) and downregulation of Notch and Hippo signaling. The EndMT phenotype of PATJ-depleted cells was associated with the nuclear recruitment of MUC1-C, YAP/TAZ, ß-catenin, and ZEB1. Our results suggest that PATJ downregulation 24 h after IS promotes EndMT, an initial step prior to secondary activation of a pro-angiogenic program. This effect is associated with functional independence suggesting that activation of EndMT shortly after stroke onset is beneficial for stroke recovery.

Evidence for the involvement of TRPV2 channels in the modulation of vascular tone in the mouse aorta.

AIMS: Transient receptor potential vanilloid 2 (TRPV2) channels are expressed in both smooth muscle and endothelial cells and participate in vascular mechanotransduction and sensing of high temperatures and lipids. Nevertheless, the impact of TRPV2 channel activation by agonists on the coordinated and cell-type specific modulation of vasoreactivity is unknown. MAIN METHODS: Aorta from 2- to 4-months-old male Oncins France 1 mice was dissected and mounted in tissue baths for isometric tension measurements. TRPV2 channel expression was assessed by immunofluorescence and western blot in mice aortas and in cultured A7r5 rat aortic smooth muscle cells. KEY FINDINGS: TRPV2 channels were expressed in all three mouse aorta layers. Activation of TRPV2 channels with probenecid evoked endothelium-dependent relaxations through a mechanism that involved activation of smooth muscle Kir and Kv channels. In addition, TRPV2 channel inhibition with tranilast increased endothelium-independent relaxations to probenecid and this effect was abrogated by the KATP channel blocker glibenclamide, revealing that smooth muscle TRPV2 channels induce negative feedback on probenecid relaxations mediated via KATP channel inhibition. Exposure to the NO donor sodium nitroprusside increased TRPV2 channel translocation to the plasma membrane in cultured smooth muscle cells and enhanced negative feedback on probenecid relaxations. SIGNIFICANCE: In conclusion, we present the first evidence that TRPV2 channels may modulate vascular tone through a balance of opposed inputs from the endothelium and the smooth muscle leading to net vasodilation. The fact that TRPV2 channel-induced activity can be amplified by NO emphasizes the pathophysiological relevance of these findings.

Cognitive biases in first-episode psychosis with and without attention-deficit/hyperactivity disorder.

Introduction: Psychotic disorders such schizophrenia and attention-deficit/hyperactivity disorder (ADHD) are neurodevelopmental disorders with social cognitive deficits. Specifically, biased interpretation of social information can result in interpersonal difficulties. Cognitive biases are prevalent in psychosis, but no previous study has investigated whether the type and severity of cognitive biases differ between subjects experiencing first-episode psychosis (FEP) with (FEP-ADHD+) and without ADHD (FEP-ADHD-). Methods: A total of 121 FEP outpatients at the Early Intervention Service of Reus were screened for childhood ADHD through the Diagnostic Interview for ADHD (DIVA). Cognitive biases were assessed by the Cognitive Biases Questionnaire for Psychosis (CBQp). CBQp scores of FEPs groups were compared with those of healthy controls (HCs) with an analysis of covariance. Spearman correlation analysis explored associations between CBQp scores and psychopathology. Results: Thirty-one FEPs met the criteria for childhood ADHD and reported significantly more cognitive bias [median (interquartile range): 47 (38-56)] than FEP-ADHD- [42 (37-48)] and HCs [38 (35.5-43)]. CBQp scores did not differ between FEP-ADHD-and HCs when adjusted for age and sex. After controlling for clinical differences, Intentionalising (F = 20.97; p < 0.001) and Emotional Reasoning biases (F = 4.17; p = 0.04) were more strongly associated with FEP-ADHD+ than FEP-ADHD-. Cognitive biases were significantly correlated with positive psychotic symptoms in both groups but only with depressive symptoms in FEP-ADHD- (r = 0.258; p = 0.03) and with poor functioning in FEP-ADHD+ (r = -0.504; p = 0.003). Conclusion: Cognitive bias severity increased from HCs to FEP-ADHD-patients to FEP-ADHD+ patients. FEP-ADHD+ patients may be a particularly vulnerable group in which metacognitive targeted interventions are needed.

Disruption of cortical cell type composition and function underlies diabetes-associated cognitive decline.

AIMS/HYPOTHESIS: Type 2 diabetes is associated with increased risk of cognitive decline although the pathogenic basis for this remains obscure. Deciphering diabetes-linked molecular mechanisms in cells of the cerebral cortex could uncover novel therapeutic targets. METHODS: Single-cell transcriptomic sequencing (scRNA-seq) was conducted on the cerebral cortex in a mouse model of type 2 diabetes (db/db mice) and in non-diabetic control mice in order to identify gene expression changes in distinct cell subpopulations and alterations in cell type composition. Immunohistochemistry and metabolic assessment were used to validate the findings from scRNA-seq and to investigate whether these cell-specific dysfunctions impact the neurovascular unit (NVU). Furthermore, the behavioural and cognitive alterations related to these dysfunctions in db/db mice were assessed via Morris water maze and novel object discrimination tests. Finally, results were validated in post-mortem sections and protein isolates from individuals with type 2 diabetes. RESULTS: Compared with non-diabetic control mice, the db/db mice demonstrated disrupted brain function as revealed by losses in episodic and spatial memory and this occurred concomitantly with dysfunctional NVU, neuronal circuitry and cerebral atrophy. scRNA-seq of db/db mouse cerebral cortex revealed cell population changes in neurons, glia and microglia linked to functional regulatory disruption including neuronal maturation and altered metabolism. These changes were validated through immunohistochemistry and protein expression analysis not just in the db/db mouse cerebral cortex but also in post-mortem sections and protein isolates from individuals with type 2 diabetes (74.3 ± 5.5 years) compared with non-diabetic control individuals (87.0 ± 8.5 years). Furthermore, metabolic and synaptic gene disruptions were evident in cortical NVU cell populations and associated with a decrease in vascular density. CONCLUSIONS/INTERPRETATION: Taken together, our data reveal disruption in the cellular and molecular architecture of the cerebral cortex induced by diabetes, which can explain, at least in part, the basis for progressive cognitive decline in individuals with type 2 diabetes. DATA AVAILABILITY: The single-cell sequencing data that supports this study are available at GEO accession GSE217665 ( https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE217665 ).

Therapeutic effect of human ApoA-I-Milano variant in aged transgenic mouse model of Alzheimer's disease.

BACKGROUND AND PURPOSE: Therapies based on apolipoprotein A-I (ApoA-I), classically tested for cardiovascular diseases, were recently proposed for Alzheimer's disease (AD). Based on a drug reprofiling approach, our objective was to explore the use of a natural variant of ApoA-I form, ApoA-I-Milano (M), as a treatment for AD. ApoA-I-M contains the R173C mutation, and confers protection against atherosclerosis development, although ApoA-I-M carriers exhibit low HDL levels. EXPERIMENTAL APPROACH: Middle-aged (12-month-old) and aged (21-month-old) APP23 mice were intraperitoneally treated for 10 weeks with human recombinant ApoA-I-M (hrApoA-I-M) protein or saline. Pathology progression through behavioural parameters and biochemical determinations was evaluated. KEY RESULTS: In middle-aged group, hrApoA-I-M treatment reduced the anxiety behaviour associated with this AD model. In aged mice, hrApoA-I-M reversed T-Maze performance alterations, a cognitive improvement accompanied by neuronal loss recovery in the dentate gyrus. Aged mice treated with hrApoA-I-M showed lower brain Aß40 soluble levels and elevated Aß40 levels in cerebrospinal fluid, without modifying insoluble brain Aß burden. Interestingly, hrApoA-I-M sub-chronic treatment induced a molecular effect on the cerebrovasculature, increasing occludin expression and ICAM-1 presence, as well as promoting an elevation of plasma soluble RAGE in all hrApoA-I-M-treated mice, drastically decreasing the AGEs/sRAGE ratio, a marker of endothelial damage. CONCLUSION AND IMPLICATIONS: Peripheral hrApoA-I-M treatment shows a beneficial impact on working memory, involving mechanisms related with brain Aß mobilization and modulation of the levels of cerebrovascular markers. Our study shows the potential therapeutic applicability of a safe and non-invasive treatment based on peripheral administration of hrApoA-I-M in AD.

The Absence of FAIM Leads to a Delay in Dark Adaptation and Hampers Arrestin-1 Translocation upon Light Reception in the Retina.

The short and long isoforms of FAIM (FAIM-S and FAIM-L) hold important functions in the central nervous system, and their expression levels are specifically enriched in the retina. We previously described that Faim knockout (KO) mice present structural and molecular alterations in the retina compatible with a neurodegenerative phenotype. Here, we aimed to study Faim KO retinal functions and molecular mechanisms leading to its alterations. Electroretinographic recordings showed that aged Faim KO mice present functional loss of rod photoreceptor and ganglion cells. Additionally, we found a significant delay in dark adaptation from early adult ages. This functional deficit is exacerbated by luminic stress, which also caused histopathological alterations. Interestingly, Faim KO mice present abnormal Arrestin-1 redistribution upon light reception, and we show that Arrestin-1 is ubiquitinated, a process that is abrogated by either FAIM-S or FAIM-L in vitro. Our results suggest that FAIM assists Arrestin-1 light-dependent translocation by a process that likely involves ubiquitination. In the absence of FAIM, this impairment could be the cause of dark adaptation delay and increased light sensitivity. Multiple retinal diseases are linked to deficits in photoresponse termination, and hence, investigating the role of FAIM could shed light onto the underlying mechanisms of their pathophysiology.

Impact of Cerebral Amyloid Angiopathy in Two Transgenic Mouse Models of Cerebral ß-Amyloidosis: A Neuropathological Study.

The pathological accumulation of parenchymal and vascular amyloid-beta (Aß) are the main hallmarks of Alzheimer's disease (AD) and Cerebral Amyloid Angiopathy (CAA), respectively. Emerging evidence raises an important contribution of vascular dysfunction in AD pathology that could partially explain the failure of anti-Aß therapies in this field. Transgenic mice models of cerebral ß-amyloidosis are essential to a better understanding of the mechanisms underlying amyloid accumulation in the cerebrovasculature and its interactions with neuritic plaque deposition. Here, our main objective was to evaluate the progression of both parenchymal and vascular deposition in APP23 and 5xFAD transgenic mice in relation to age and sex. We first showed a significant age-dependent accumulation of extracellular Aß deposits in both transgenic models, with a greater increase in APP23 females. We confirmed that CAA pathology was more prominent in the APP23 mice, demonstrating a higher progression of Aß-positive vessels with age, but not linked to sex, and detecting a pronounced burden of cerebral microbleeds (cMBs) by magnetic resonance imaging (MRI). In contrast, 5xFAD mice did not present CAA, as shown by the negligible Aß presence in cerebral vessels and the occurrence of occasional cMBs comparable to WT mice. In conclusion, the APP23 mouse model is an interesting tool to study the overlap between vascular and parenchymal Aß deposition and to evaluate future disease-modifying therapy before its translation to the clinic.

Faim knockout leads to gliosis and late-onset neurodegeneration of photoreceptors in the mouse retina.

Fas Apoptotic Inhibitory Molecule protein (FAIM) is a death receptor antagonist and an apoptosis regulator. It encodes two isoforms, namely FAIM-S (short) and FAIM-L (long), both with significant neuronal functions. FAIM-S, which is ubiquitously expressed, is involved in neurite outgrowth. In contrast, FAIM-L is expressed only in neurons and it protects them from cell death. Interestingly, FAIM-L is downregulated in patients and mouse models of Alzheimer's disease before the onset of neurodegeneration, and Faim transcript levels are decreased in mouse models of retinal degeneration. However, few studies have addressed the role of FAIM in the central nervous system, yet alone the retina. The retina is a highly specialized tissue, and its degeneration has proved to precede pathological mechanisms of neurodegenerative diseases. Here we describe that Faim depletion in mice damages the retina persistently and leads to late-onset photoreceptor death in older mice. Immunohistochemical analyses showed that Faim knockout (Faim-/- ) mice present ubiquitinated aggregates throughout the retina from early ages. Moreover, retinal cells released stress signals that can signal to Müller cells, as shown by immunofluorescence and qRT-PCR. Müller cells monitor retinal homeostasis and trigger a gliotic response in Faim-/- mice that becomes pathogenic when sustained. In this regard, we observed pronounced vascular leakage at later ages, which may be caused by persistent inflammation. These results suggest that FAIM is an important player in the maintenance of retinal homeostasis, and they support the premise that FAIM is a plausible early marker for late photoreceptor and neuronal degeneration.

MFG-E8 (LACTADHERIN): a novel marker associated with cerebral amyloid angiopathy.

Brain accumulation of amyloid-beta (Aß) is a crucial feature in Alzheimer´s disease (AD) and cerebral amyloid angiopathy (CAA), although the pathophysiological relationship between these diseases remains unclear. Numerous proteins are associated with Aß deposited in parenchymal plaques and/or cerebral vessels. We hypothesized that the study of these proteins would increase our understanding of the overlap and biological differences between these two pathologies and may yield new diagnostic tools and specific therapeutic targets. We used a laser capture microdissection approach combined with mass spectrometry in the APP23 transgenic mouse model of cerebral-ß-amyloidosis to specifically identify vascular Aß-associated proteins. We focused on one of the main proteins detected in the Aß-affected cerebrovasculature: MFG-E8 (milk fat globule-EGF factor 8), also known as lactadherin. We first validated the presence of MFG-E8 in mouse and human brains. Immunofluorescence and immunoblotting studies revealed that MFG-E8 brain levels were higher in APP23 mice than in WT mice. Furthermore, MFG-E8 was strongly detected in Aß-positive vessels in human postmortem CAA brains, whereas MFG-E8 was not present in parenchymal Aß deposits. Levels of MFG-E8 were additionally analysed in serum and cerebrospinal fluid (CSF) from patients diagnosed with CAA, patients with AD and control subjects. Whereas no differences were found in MFG-E8 serum levels between groups, MFG-E8 concentration was significantly lower in the CSF of CAA patients compared to controls and AD patients. Finally, in human vascular smooth muscle cells MFG-E8 was protective against the toxic effects of the treatment with the Aß40 peptide containing the Dutch mutation. In summary, our study shows that MFG-E8 is highly associated with CAA pathology and highlights MFG-E8 as a new CSF biomarker that could potentially be used to differentiate cerebrovascular Aß pathology from parenchymal Aß deposition.

SSAO/VAP-1 in Cerebrovascular Disorders: A Potential Therapeutic Target for Stroke and Alzheimer's Disease.

The semicarbazide-sensitive amine oxidase (SSAO), also known as vascular adhesion protein-1 (VAP-1) or primary amine oxidase (PrAO), is a deaminating enzyme highly expressed in vessels that generates harmful products as a result of its enzymatic activity. As a multifunctional enzyme, it is also involved in inflammation through its ability to bind and promote the transmigration of circulating leukocytes into inflamed tissues. Inflammation is present in different systemic and cerebral diseases, including stroke and Alzheimer's disease (AD). These pathologies show important affectations on cerebral vessels, together with increased SSAO levels. This review summarizes the main roles of SSAO/VAP-1 in human physiology and pathophysiology and discusses the mechanisms by which it can affect the onset and progression of both stroke and AD. As there is an evident interrelationship between stroke and AD, basically through the vascular system dysfunction, the possibility that SSAO/VAP-1 could be involved in the transition between these two pathologies is suggested. Hence, its inhibition is proposed to be an interesting therapeutical approach to the brain damage induced in these both cerebral pathologies.

FAIM-L - SIVA-1: Two Modulators of XIAP in Non-Apoptotic Caspase Function.

Apoptosis is crucial for the correct development of the nervous system. In adulthood, the same protein machinery involved in programmed cell death can control neuronal adaptiveness through modulation of synaptic pruning and synaptic plasticity processes. Caspases are the main executioners in these molecular pathways, and their strict regulation is essential to perform neuronal remodeling preserving cell survival. FAIM-L and SIVA-1 are regulators of caspase activation. In this review we will focus on FAIM-L and SIVA-1 as two functional antagonists that modulate non-apoptotic caspase activity in neurons. Their participation in long-term depression and neurite pruning will be described in base of the latest studies performed. In addition, the association of FAIM-L non-apoptotic functions with the neurodegeneration process will be reviewed.

Sensing of nutrients by CPT1C controls SAC1 activity to regulate AMPA receptor trafficking.

Carnitine palmitoyltransferase 1C (CPT1C) is a sensor of malonyl-CoA and is located in the ER of neurons. AMPA receptors (AMPARs) mediate fast excitatory neurotransmission in the brain and play a key role in synaptic plasticity. In the present study, we demonstrate across different metabolic stress conditions that modulate malonyl-CoA levels in cortical neurons that CPT1C regulates the trafficking of the major AMPAR subunit, GluA1, through the phosphatidyl-inositol-4-phosphate (PI(4)P) phosphatase SAC1. In normal conditions, CPT1C down-regulates SAC1 catalytic activity, allowing efficient GluA1 trafficking to the plasma membrane. However, under low malonyl-CoA levels, such as during glucose depletion, CPT1C-dependent inhibition of SAC1 is released, facilitating SAC1's translocation to ER-TGN contact sites to decrease TGN PI(4)P pools and trigger GluA1 retention at the TGN. Results reveal that GluA1 trafficking is regulated by CPT1C sensing of malonyl-CoA and provide the first report of a SAC1 inhibitor. Moreover, they shed light on how nutrients can affect synaptic function and cognition.

Relación entre el maltrato infantil y la adaptación social en una muestra de jóvenes atendidos en un servicio de intervención precoz en psicosis / Relationship between childhood trauma and social adaptation in a sample of young people attending an early intervention service for psychosis

INTRODUCCIÓN: El maltrato infantil se ha asociado a un mayor riesgo de psicosis, a una mayor severidad en síntomas psicopatológicos y a un peor pronóstico funcional en pacientes con un trastorno psicótico. El presente estudio pretende evaluar la relación entre el maltrato infantil, psicopatología y la adaptación social en una muestra de primeros episodios psicóticos (PEP) y de estados mentales de alto riesgo (EMAR). MATERIAL Y MÉTODOS: La muestra incluyó 114 jóvenes (18-35 años, 81 PEP y 33 EMAR) atendidos en un Servicio de Intervención Precoz en Psicosis. Se evaluaron síntomas positivos, negativos y depresivos con las escalas PANSS y Calgary de Depresión; los antecedentes de maltrato infantil con el Childhood Trauma Questionnaire; la adaptación social con la Escala Autoaplicada de Adaptación Social (SASS). Se utilizó el modelo de ecuaciones estructurales (SEM) para explorar relaciones entre psicopatología, maltrato infantil y dimensiones de la SASS en toda la muestra (incluyendo PEP y EMAR). Se repitió un análisis SEM exploratorio en la submuestra de PEP. RESULTADOS: Los EMAR presentaron más negligencia emocional y peor adaptación social, comparados con los PEP. El SEM muestra que el maltrato se asocia con una peor adaptación social en todos los dominios, de forma directa en dominios que implican relaciones interpersonales, y por una vía mediada por síntomas depresivos en los dominios que implican ocio y trabajo e intereses socioculturales. CONCLUSIONES: El maltrato infantil tiene un efecto negativo sobre la adaptación social en jóvenes en fases tempranas de las psicosis. Los síntomas depresivos son mediadores de una peor adaptación en aspectos funcionales relacionados con el ocio y el trabajo

INTRODUCTION: Childhood trauma has been associated with an increased risk of psychosis, a greater severity of psychopathological symptoms, and a worse functional prognosis in patients with psychotic disorders. The current study aims to explore the relationship between childhood trauma, psychopathology and social adaptation in a sample of young people with first episode psychosis (FEP) or at-risk mental states (ARMS). MATERIAL AND METHODS: The sample included 114 young people (18-35 years old, 81 FEP and 33 ARMS) who were attending an Early Intervention Service for Psychosis. Positive, negative and depressive symptoms were assessed with the PANSS and the Calgary Depression Scale; history of childhood trauma was assessed with the Childhood Trauma Questionnaire; social adaptation was assessed with the Social Adaptation Self-evaluation Scale (SASS). Structural equation modeling (SEM) was used to explore the relationship between childhood trauma, psychopathology and SASS dimensions in the global sample (including FEP and ARMS). An exploratory SEM analysis was repeated in the subsample of FEP patients. RESULTS: ARMS individuals reported more emotional neglect and worse social adaptation compared to FEP. SEM analysis showed that childhood trauma is associated with a worse social adaptation, in a direct way with domains involving interpersonal relationships, and mediated by depressive symptoms with those domains involving leisure, work and socio-cultural interests. CONCLUSIONS: Childhood trauma has a negative effect on social adaptation in young people with early psychosis. Depressive symptoms play a mediation role in this association, especially in domains of leisure and work

Relationship between childhood trauma and social adaptation in a sample of young people attending an early intervention service for psychosis. / Relación entre el maltrato infantil y la adaptación social en una muestra de jóvenes atendidos en un servicio de intervención precoz en psicosis.

INTRODUCTION: Childhood trauma has been associated with an increased risk of psychosis, a greater severity of psychopathological symptoms, and a worse functional prognosis in patients with psychotic disorders. The current study aims to explore the relationship between childhood trauma, psychopathology and social adaptation in a sample of young people with first episode psychosis (FEP) or at-risk mental states (ARMS). MATERIAL AND METHODS: The sample included 114 young people (18-35 years old, 81 FEP and 33 ARMS) who were attending an Early Intervention Service for Psychosis. Positive, negative and depressive symptoms were assessed with the PANSS and the Calgary Depression Scale; history of childhood trauma was assessed with the Childhood Trauma Questionnaire; social adaptation was assessed with the Social Adaptation Self-evaluation Scale (SASS). Structural equation modeling (SEM) was used to explore the relationship between childhood trauma, psychopathology and SASS dimensions in the global sample (including FEP and ARMS). An exploratory SEM analysis was repeated in the subsample of FEP patients. RESULTS: ARMS individuals reported more emotional neglect and worse social adaptation compared to FEP. SEM analysis showed that childhood trauma is associated with a worse social adaptation, in a direct way with domains involving interpersonal relationships, and mediated by depressive symptoms with those domains involving leisure, work and socio-cultural interests. CONCLUSIONS: Childhood trauma has a negative effect on social adaptation in young people with early psychosis. Depressive symptoms play a mediation role in this association, especially in domains of leisure and work.

Glycated Haemoglobin Is Associated With Poorer Cognitive Performance in Patients With Recent-Onset Psychosis.

BACKGROUND: Glucose abnormalities and cognitive alterations are present before the onset of schizophrenia. We aimed to study whether glucose metabolism parameters are associated with cognitive functioning in recent-onset psychosis (ROP) patients while adjusting for hypothalamic-pituitary adrenal (HPA) axis measures. METHODS: Sixty ROP outpatients and 50 healthy subjects (HS) were studied. Cognitive function was assessed with the MATRICS Consensus Cognitive Battery. Glycated haemoglobin (HbA1c), glucose, insulin, and C-peptide levels were determined in plasma. The HOMA-insulin resistance index was calculated. Salivary samples were obtained at home on another day to assess the cortisol awakening response and cortisol levels during the day. Univariate analyses were conducted to explore the association between glucose metabolism parameters and cognitive tasks. For those parameters that were more clearly associated with the cognitive outcome, multiple linear regression analyses were conducted to adjust for covariates. Each cognitive task was considered the dependent variable. Covariates were age, sex, education level, diagnosis, antipsychotic and benzodiazepine treatment, body mass index (BMI), smoking, and HPA axis measures. Potential interactions between diagnosis and glucose parameters were tested. RESULTS: There were no significant differences in HPA axis measures or glucose parameters, with the exception of C-peptide (that was higher in ROP patients), between groups. ROP patients had a lower performance than HS in all cognitive tasks (p < 0.01 for all tasks). Of all glucose metabolism parameters, HbA1c levels were more clearly associated with cognitive impairment in cognitive tasks dealing with executive functions and visual memory in both ROP patients and HS. Multivariate analyses found a significant negative association between HbA1c and cognitive functioning in five cognitive tasks dealing with executive functions, visual memory and attention/vigilance (a ROP diagnosis by HbA1c negative interaction was found in this latter cognitive domain, suggesting that HBA1c levels are associated with impaired attention only in ROP patients). CONCLUSIONS: Our study found that HbA1c was negatively associated with cognitive functioning in both ROP patients and HS in tasks dealing with executive functions and visual memory. In ROP patients, HbA1c was also associated with impaired attention. These results were independent of BMI and measures of HPA axis activity.

Clinical and cognitive correlates of childhood attention-deficit/hyperactivity disorder in first-episode psychosis: A controlled study.

The relationship between childhood attention-deficit/hyperactivity disorder (c-ADHD) and psychosis has been understudied. Cognitive dysfunction is a core feature of both disorders, but no previous study has investigated whether first-episode psychosis (FEP) with c-ADHD (FEP-ADHD+) presents a different cognitive profile than FEP without c-ADHD (FEP-ADHD-). One hundred and thirty-three FEP outpatients were screened for c-ADHD through a diagnostic interview and underwent a comprehensive clinical and cognitive assessment with the MATRICS Consensus Cognitive Battery (MCCB). Cognitive differences among FEP groups, and a group of 65 healthy controls (HCs) were analysed by multivariate analysis of covariance. Nearly 25% of FEP fulfilled criteria for c-ADHD. Both FEP groups performed worse than HCs in speed processing, executive function and social cognition, but only the FEP-ADHD+group was significantly more impaired than the HC group in attention (F = 4.35; p = 0.04). Only the Trail Making Test A (TMT-A) (F = 6.99; p = 0.01) within the domain of processing speed and the Neuropsychological Assessment Battery (NAB) (F = 6.46; p = 0.01) within the domain of executive function reliably differentiated the two clinical groups. The FEP groups did not differ in the severity of psychopathology, but the FEP-ADHD+reported fewer years of education than the FEP-ADHD- and were more likely to use tobacco and cannabis and to require higher doses of antipsychotics to achieve a clinical response. In conclusion, we found a gradient of severity in cognitive performance between groups, with FEP-ADHD+ having the greatest cognitive impairment. Our results suggest that FEP-ADHD+ represents a subgroup with a worse prognosis than FEP-ADHD-.

Proteasomal-Mediated Degradation of AKAP150 Accompanies AMPAR Endocytosis during cLTD.

The number and function of synaptic AMPA receptors (AMPARs) tightly regulates excitatory synaptic transmission. Current evidence suggests that AMPARs are inserted into the postsynaptic membrane during long-term potentiation (LTP) and are removed from the membrane during long-term depression (LTD). Dephosphorylation of GluA1 at Ser-845 and enhanced endocytosis are critical events in the modulation of LTD. Moreover, changes in scaffold proteins from the postsynaptic density (PSD) could be also related to AMPAR regulation in LTD. In the present study we analyzed the effect of chemical LTD (cLTD) on A-kinase anchoring protein (AKAP)150 and AMPARs levels in mouse-cultured neurons. We show that cLTD induces AKAP150 protein degradation via proteasome, coinciding with GluA1 dephosphorylation at Ser-845 and endocytosis of GluA1-containing AMPARs. Pharmacological inhibition of proteasome activity, but not phosphatase calcineurin (CaN), reverted cLTD-induced AKAP150 protein degradation. Importantly, AKAP150 silencing induced dephosphorylation of GluA1 Ser-845 and GluA1-AMPARs endocytosis while AKAP150 overexpression blocked cLTD-mediated GluA1-AMPARs endocytosis. Our results provide direct evidence that cLTD-induced AKAP150 degradation by the proteasome contributes to synaptic AMPARs endocytosis.

Association between anti-thyroid antibodies and negative symptoms in early psychosis.

AIM: In the current cross-sectional study, we aimed to explore whether thyroid function or thyroid autoimmunity are associated with psychopathological symptoms and social functioning in patients with early psychosis. We hypothesized that psychopathological severity is greater in those patients with positive thyroid autoimmunity. METHODS: We studied 70 outpatients with early psychosis (<3 years of illness) and 37 healthy subjects. Psychopathological symptoms (positive, negative, disorganized, excited and depressive) and social functioning were assessed. Thyroid autoimmunity (antibodies against thyroid peroxidase [TPO-Abs] and thyroglobulin [TG-Abs]) and thyroid function (thyroid-stimulating hormone [TSH] and free thyroxin [FT4]) were determined. Associations of thyroid variables and psychometric measures were assessed with Spearman's correlations. Logistic regression was performed to explore the association between psychopathological symptoms and positive anti-thyroidal antibodies while adjusting for covariates. RESULTS: When compared to patients without thyroid antibodies, those with positive thyroid antibodies had more negative symptoms and poorer function (P < .05). Titres of TPO-Abs were significantly correlated with negative and depressive PANSS domains and poorer functioning. TG-Abs were also associated with poorer functioning but not with psychopathological symptoms. TSH and FT4 concentrations were not associated with clinical symptoms. In the logistic regression analysis adjusted for age, gender, antipsychotic treatment, lithium, TSH and FT4 concentrations, negative symptoms were associated with thyroid autoimmunity (OR = 1.2, P = .019). CONCLUSIONS: Our study suggests that anti-thyroid antibodies are associated with a more severe phenotype with increased negative symptoms and poorer functioning in early psychotic patients. Since causality cannot be inferred with cross-sectional data, future longitudinal studies are needed to overcome this limitation.

Hypothalamic-pituitary-adrenal axis function and exposure to stress factors and cannabis use in recent-onset psychosis.

Objectives: Previous studies suggest that childhood trauma, stressful life events, and cannabis use are associated with psychosis. We aimed to explore whether these environmental factors have an effect on hypothalamic-pituitary-adrenal (HPA) axis indices in recent-onset psychosis.Methods: We studied 56 recent-onset psychosis outpatients and 47 healthy controls. Childhood trauma was assessed with the Childhood Trauma Questionnaire. Stressful life events were assessed with the Holmes-Rahe Social Readjustment Scale. Cannabis use was assessed by semistructured interviews. Several HPA axis measures were analysed in saliva: cortisol awakening response (CAR), diurnal cortisol slope, and dexamethasone suppression test ratio (DSTR) after 0.25 mg of dexamethasone. Multiple linear regression analyses were conducted to explore the contribution of environmental factors to each HPA axis measure while adjusting for covariates (diagnosis, age, gender, smoking, body mass index and treatments).Results: There were no significant differences in HPA axis measures between diagnostic groups. Cannabis use was associated with a more flattened diurnal cortisol slope (standardized ß = 0.21, p = 0.038), independent of recent-onset psychosis diagnosis. No associations were found between environmental factors and other HPA axis measures (CAR, DSTR).Conclusions: Our study provides evidence for the effect of cannabis exposure in cortisol secretion patterns in both healthy controls and recent-onset psychosis patients.

Blood-brain barrier dysfunction underlying Alzheimer's disease is induced by an SSAO/VAP-1-dependent cerebrovascular activation with enhanced Aß deposition.

Dysfunctions of the vascular system directly contribute to the onset and progression of Alzheimer's disease (AD). The blood-brain barrier (BBB) shows signs of malfunction at early stages of the disease. When Abeta peptide (Aß) is deposited on brain vessels, it induces vascular degeneration by producing reactive oxygen species and promoting inflammation. These molecular processes are also related to an excessive SSAO/VAP-1 (semicarbazide-sensitive amine oxidase) enzymatic activity, observed in plasma and in cerebrovascular tissue of AD patients. We studied the contribution of vascular SSAO/VAP-1 to the BBB dysfunction in AD using in vitro BBB models. Our results show that SSAO/VAP-1 expression is associated to endothelial activation by altering the release of pro-inflammatory and pro-angiogenic angioneurins, most highly IL-6, IL-8 and VEGF. It is also related to a BBB structure alteration, with a decrease in tight-junction proteins such as zona occludens or claudin-5. Moreover, the BBB function reveals increased permeability and leukocyte adhesion in cells expressing SSAO/VAP-1, as well as an enhancement of the vascular Aß deposition induced by mechanisms both dependent and independent of the enzymatic activity of SSAO/VAP-1. These results reveal an interesting role of vascular SSAO/VAP-1 in BBB dysfunction related to AD progression, opening a new window in the search of alternative therapeutic targets for fighting AD.