Developmental imaging studies show that cortical grey matter decreases in volume during childhood and adolescence. However, considerably less research has addressed the development of subcortical ...regions (caudate, putamen, pallidum, accumbens, thalamus, amygdala, hippocampus and the cerebellar cortex), in particular not in longitudinal designs. We used the automatic labeling procedure in FreeSurfer to estimate the developmental trajectories of the volume of these subcortical structures in 147 participants (age 7.0–24.3years old, 94 males; 53 females) of whom 53 participants were scanned twice or more. A total of 223 magnetic resonance imaging (MRI) scans (acquired at 1.5-T) were analyzed. Substantial diversity in the developmental trajectories was observed between the different subcortical gray matter structures: the volume of caudate, putamen and nucleus accumbens decreased with age, whereas the volume of hippocampus, amygdala, pallidum and cerebellum showed an inverted U-shaped developmental trajectory. The thalamus showed an initial small increase in volume followed by a slight decrease. All structures had a larger volume in males than females over the whole age range, except for the cerebellum that had a sexually dimorphic developmental trajectory. Thus, subcortical structures appear to not yet be fully developed in childhood, similar to the cerebral cortex, and continue to show maturational changes into adolescence. In addition, there is substantial heterogeneity between the developmental trajectories of these structures.
•Development of subcortical structures was examined in 150 typically developing children.•Similar to the cerebral cortex, subcortical structures are not yet fully developed in childhood.•There was substantial heterogeneity in developmental trajectories of subcortical structures.•All structures were larger in males than females over the whole age range.•The cerebellum was the only structure to show a sexually dimorphic trajectory.
Indoleamine 2,3-dioxygenase 2 (IDO2) is a paralog of Indoleamine 2,3-dioxygenase 1 (IDO1), a tryptophan-degrading enzyme producing immunomodulatory molecules. However, the two proteins are unlikely ...to carry out the same functions. IDO2 shows little or no tryptophan catabolic activity and exerts contrasting immunomodulatory roles in a context-dependent manner in cancer and autoimmune diseases. The recently described potential non-enzymatic activity of IDO2 has suggested its possible involvement in alternative pathways, resulting in either pro- or anti-inflammatory effects in different models. In a previous study on non-small cell lung cancer (NSCLC) tissues, we found that IDO2 expression revealed at the plasma membrane level of tumor cells was significantly associated with poor prognosis. In this study, the A549 human cell line, basally expressing IDO2, was used as an in vitro model of human lung adenocarcinoma to gain more insights into a possible alternative function of IDO2 different from the catalytic one. In these cells, immunocytochemistry and isopycnic sucrose gradient analyses confirmed the IDO2 protein localization in the cell membrane compartment, and the immunoprecipitation of tyrosine-phosphorylated proteins revealed that kinase activities can target IDO2. The different localization from the cytosolic one and the phosphorylation state are the first indications for the signaling function of IDO2, suggesting that the IDO2 non-enzymatic role in cancer cells is worthy of deeper understanding.
Src is a protein tyrosine kinase commonly activated downstream of transmembrane receptors and plays key roles in cell growth, migration, and survival signaling pathways. In conventional dendritic ...cells (cDCs), Src is involved in the activation of the non-enzymatic functions of indoleamine 2,3-dioxygenase 1 (IDO1), an immunoregulatory molecule endowed with both catalytic activity and signal transducing properties. Prompted by the discovery that the metabolite spermidine confers a tolerogenic phenotype on cDCs that is dependent on both the expression of IDO1 and the activity of Src kinase, we here investigated the spermidine mode of action. We found that spermidine directly binds Src in a previously unknown allosteric site located on the backside of the SH2 domain and thus acts as a positive allosteric modulator of the enzyme. Besides confirming that Src phosphorylates IDO1, here we showed that spermidine promotes the protein–protein interaction of Src with IDO1. Overall, this study may pave the way toward the design of allosteric modulators able to switch on/off the Src-mediated pathways, including those involving the immunoregulatory protein IDO1.
The tryptophan-degrading enzyme indoleamine 2,3-dioxygenase 1 (IDO1) is a plastic immune checkpoint molecule that potently orchestrates immune responses within the tumor microenvironment (TME). As a ...heme-containing protein, IDO1 catalyzes the conversion of the essential amino acid tryptophan into immunoactive metabolites, called kynurenines. By depleting tryptophan and enriching the TME with kynurenines, IDO1 catalytic activity shapes an immunosuppressive TME. Accordingly, the inducible or constitutive IDO1 expression in cancer correlates with a negative prognosis for patients, representing one of the critical tumor-escape mechanisms. However, clinically trialed IDO1 catalytic inhibitors disappointed the expected anti-tumor efficacy. Interestingly, the non-enzymatic apo-form of IDO1 is still active as a transducing protein, capable of promoting an immunoregulatory phenotype in dendritic cells (DCs) as well as a pro-tumorigenic behavior in murine melanoma. Moreover, the IDO1 catalytic inhibitor epacadostat can induce a tolerogenic phenotype in plasmacytoid DCs, overcoming the catalytic inhibition of IDO1. Based on this recent evidence, IDO1 plasticity was investigated in the human ovarian cancer cell line, SKOV-3, that constitutively expresses IDO1 in a dynamic balance between the holo- and apo-protein, and thus potentially endowed with a dual function (i.e., enzymatic and non-enzymatic). Besides inhibiting the catalytic activity, epacadostat persistently stabilizes the apo-form of IDO1 protein, favoring its tyrosine-phosphorylation and promoting its association with the phosphatase SHP-2. In SKOV-3 cells, both these early molecular events activate a signaling pathway transduced by IDO1 apo-protein, which is independent of its catalytic activity and contributes to the tumorigenic phenotype of SKOV-3 cells. Overall, our findings unveiled a new mechanism of action of epacadostat on IDO1 target, repositioning the catalytic inhibitor as a stabilizer of the apo-form of IDO1, still capable of transducing a pro-tumorigenic pathway in SKOV-3 tumor. This mechanism could contribute to clarify the lack of effectiveness of epacadostat in clinical trials and shed light on innovative immunotherapeutic strategies to tackle IDO1 target.
The excitatory/inhibitory (E/I) imbalance hypothesis posits that imbalance between excitatory (glutamatergic) and inhibitory (GABAergic) mechanisms underlies the behavioral characteristics of autism. ...However, how E/I imbalance arises and how it may differ across autism symptomatology and brain regions is not well understood. We used innovative analysis methods-combining competitive gene-set analysis and gene-expression profiles in relation to cortical thickness (CT) to investigate relationships between genetic variance, brain structure and autism symptomatology of participants from the AIMS-2-TRIALS LEAP cohort (autism = 359, male/female = 258/101; neurotypical control participants = 279, male/female = 178/101) aged 6-30 years. Using competitive gene-set analyses, we investigated whether aggregated genetic variation in glutamate and GABA gene-sets could be associated with behavioral measures of autism symptoms and brain structural variation. Further, using the same gene-sets, we corelated expression profiles throughout the cortex with differences in CT between autistic and neurotypical control participants, as well as in separate sensory subgroups. The glutamate gene-set was associated with all autism symptom severity scores on the Autism Diagnostic Observation Schedule-2 (ADOS-2) and the Autism Diagnostic Interview-Revised (ADI-R) within the autistic group. In adolescents and adults, brain regions with greater gene-expression of glutamate and GABA genes showed greater differences in CT between autistic and neurotypical control participants although in opposing directions. Additionally, the gene expression profiles were associated with CT profiles in separate sensory subgroups. Our results suggest complex relationships between E/I related genetics and autism symptom profiles as well as brain structure alterations, where there may be differential roles for glutamate and GABA.
The mammillary bodies may be small, but they have an important role in encoding complex memories. Mammillary body pathology often occurs following thiamine deficiency but there is increasing evidence ...that the mammillary bodies are also compromised in other neurological conditions and in younger ages groups. For example, the mammillary bodies are frequently affected in neonates with hypoxic-ischemic encephalopathy. At present, there is no normative data for the mammillary bodies in younger groups making it difficult to identify abnormalities in neurological disorders. To address this, the present study set out to develop a normative dataset for neonates and for children to young adult. A further aim was to determine whether there were laterality or sex differences in mammillary body volumes. Mammillary body volumes were obtained from MRI scans from 506 participants across two datasets. Measures for neonates were acquired from the Developing Human Connectome Project database (156 male; 100 female); volumes for individuals aged 6–24 were acquired from the NICHE database (166 males; 84 females). Volume measurements were acquired using a semi-automated multi-atlas segmentation approach. Mammillary body volumes increased up to approximately 15 years-of-age. The left mammillary body was marginally, but significantly, larger than the right in the neonates with a similar pattern in older children/young adults. In neonates, the mammillary bodies in males were slightly bigger than females but no sex differences were present in older children/young adults. Given the increasing presentation of mammillary body pathology in neonates and children, these normative data will enable better assessment of the mammillary bodies in healthy and at-risk populations.
•Normative volume data are presented for the mammillary bodies for neonates and for age 6–24.•The mammillary bodies show the greatest growth trajectory during the neonatal period.•Mammillary bodies are larger in males than females in neonates but there is no effect of sex in children/young adults.•The left mammillary body is larger than the right mammillary body in neonates and older children/young adults.
•Neuroradiological findings are more common in autism spectrum disorder and tend to cluster.•Neuroradiological findings are not specific to autism spectrum disorder.•Neuroradiological findings may ...point toward developmental processes involved.•Qualitative screening of brain MRI scans complements quantitative morphometry.
Autism spectrum disorder (ASD) is a group of neurodevelopmental conditions associated with quantitative differences in cortical and subcortical brain morphometry. Qualitative assessment of brain morphology provides complementary information on the possible underlying neurobiology. Studies of neuroradiological findings in ASD have rendered mixed results, and await robust replication in a sizable and independent sample.
We systematically and comprehensively assessed neuroradiological findings in a large cohort of participants with ASD and age-matched controls (total N = 620, 348 ASD and 272 controls), including 70 participants with intellectual disability (47 ASD, 23 controls). We developed a comprehensive scoring system, augmented by standardized biometric measures.
There was a higher incidence of neuroradiological findings in individuals with ASD (89.4 %) compared to controls (83.8 %, p = .042). Certain findings were also more common in ASD, in particular opercular abnormalities (OR 1.9, 95 % CI 1.3–3.6) and mega cisterna magna (OR 2.4, 95 % CI 1.4–4.0) reached significance when using FDR, whereas increases in macrocephaly (OR 2.0, 95 % CI 1.2–3.2), cranial deformities (OR 2.4, 95 % CI: 1.0–5.8), calvarian / dural thickening (OR 1.5, 95 % CI 1.0–2.3), ventriculomegaly (OR 3.4, 95 % CI 1.3–9.2), and hypoplasia of the corpus callosum (OR 2.7, 95 % CI 1.1–6.3) did not survive this correction. Furthermore, neuroradiological findings were more likely to occur in isolation in controls, whereas they clustered more frequently in ASD. The incidence of neuroradiological findings was higher in individuals with mild intellectual disability (95.7 %), irrespective of ASD diagnosis.
There was a subtly higher prevalence of neuroradiological findings in ASD, which did not appear to be specific to the condition. Individual findings or clusters of findings may point towards the neurodevelopmental mechanisms involved in individual cases. As such, clinical MRI assessments may be useful to guide further etiopathological (genetic) investigations, and are potentially valuable to fundamental ASD research.
Studies of Attention-Deficit/Hyperactivity Disorder (ADHD) have shown developmental changes in the cortical mantle. Different dimensions of cortical morphology, such as surface area and thickness, ...relate to different neurodevelopmental mechanisms. As such, studying multiple dimensions may inform us about the developmental origins of ADHD. Furthermore, results from existing longitudinal samples await replication. Therefore, we conducted a longitudinal study of multiple cortical dimensions in a sizable, independent ADHD sample. We analyzed 297 anatomical MRI scans from two matched groups of 94 subjects with ADHD and 94 controls, aged 6-28 years. We estimated the developmental trajectories of cortical volume, surface, thickness and gyrification for 68 regions using mixed-effects regression analysis. Subjects with ADHD had smaller overall cortical volume, predominantly driven by decreases in frontal lobe volume that were associated with reduced surface area and gyrification. Nearly all decreases were stable across development. Only a few decreases survived stringent Bonferroni correction for multiple comparisons, with the smallest detectable Cohen's d |0.43|. There were no between-group differences in cortical thickness, or in subcortical volumes. Our results suggest that ADHD is associated with developmentally persistent reductions in frontal cortical volume, surface area, and gyrification. This may implicate early neurodevelopmental mechanisms regulating cortical expansion and convolution in ADHD.
Autism spectrum disorder (ASD) is accompanied by highly individualized neuroanatomical deviations that potentially map onto distinct genotypes and clinical phenotypes. This study aimed to link ...differences in brain anatomy to specific biological pathways to pave the way toward targeted therapeutic interventions.
The authors examined neurodevelopmental differences in cortical thickness and their genomic underpinnings in a large and clinically diverse sample of 360 individuals with ASD and 279 typically developing control subjects (ages 6-30 years) within the EU-AIMS Longitudinal European Autism Project (LEAP). The authors also examined neurodevelopmental differences and their potential pathophysiological mechanisms between clinical ASD subgroups that differed in the severity and pattern of sensory features.
In addition to significant between-group differences in "core" ASD brain regions (i.e., fronto-temporal and cingulate regions), individuals with ASD manifested as neuroanatomical outliers within the neurotypical cortical thickness range in a wider neural system, which was enriched for genes known to be implicated in ASD on the genetic and/or transcriptomic level. Within these regions, the individuals' total (i.e., accumulated) degree of neuroanatomical atypicality was significantly correlated with higher polygenic scores for ASD and other psychiatric conditions, and it scaled with measures of symptom severity. Differences in cortical thickness deviations were also associated with distinct sensory subgroups, especially in brain regions expressing genes involved in excitatory rather than inhibitory neurotransmission.
The study findings corroborate the link between macroscopic differences in brain anatomy and the molecular mechanisms underpinning heterogeneity in ASD, and provide future targets for stratification and subtyping.
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