The 22q11.2 deletion syndrome (22q11.2DS) is a neurodevelopmental disorder associated with a number of volumetric brain abnormalities. The syndrome is also associated with an increased risk for ...neuropsychiatric disorders including schizophrenia and autism spectrum disorder. An earlier meta-analysis showed reduced grey and white matter volumes in individuals with 22q11.2DS. Since this analysis was conducted, the number of studies has increased markedly, permitting more precise estimates of effects and more regions to be examined. Although 22q11.2DS is clinically heterogeneous, it is not known to what extent this heterogeneity is mirrored in neuroanatomy. The aim of this study was thus to investigate differences in mean brain volume and structural variability within regions, between 22q11.2DS and typically developing controls. We examined studies that reported measures of brain volume using MRI in PubMed, Web of Science, Scopus and PsycINFO from inception to 1 May 2019. Data were extracted from studies in order to calculate effect sizes representing case-control difference in mean volume, and in the variability of volume (as measured using the log variability ratio (lnVR) and coefficient of variation ratio (CVR)). We found significant overall decreases in mean volume in 22q11.2DS compared with control for: total brain (g = -0.96; p < 0.001); total grey matter (g = -0.81, p < 0.001); and total white matter (g = -0.81; p < 0.001). There was also a significant overall reduction of mean volume in 22q11.2DS subjects compared with controls in frontal lobe (g = -0.47; p < 0.001), temporal lobe (g = -0.84; p < 0.001), parietal lobe (g = -0.73; p = 0.053), cerebellum (g = -1.25; p < 0.001) and hippocampus (g = -0.90; p < 0.001). Significantly increased variability in 22q11.2DS individuals compared with controls was found only for the hippocampus (VR, 1.14; p = 0.036; CVR, 1.30; p < 0.001), and lateral ventricles (VR, 1.56; p = 0.004). The results support the notion that structural abnormalities in 22q11.2DS and schizophrenia are convergent, and also to some degree with findings in autism spectrum disorder. Finally, the increased variability seen in the hippocampus in 22q11.2DS may underlie some of the heterogeneity observed in the neuropsychiatric phenotype.
Germline mutations in the BRCA2 tumour suppressor are associated with both an increased lifetime risk of developing prostate cancer (PCa) and increased risk of aggressive disease. To understand this ...aggression, here we profile the genomes and methylomes of localized PCa from 14 carriers of deleterious germline BRCA2 mutations (BRCA2-mutant PCa). We show that BRCA2-mutant PCa harbour increased genomic instability and a mutational profile that more closely resembles metastastic than localized disease. BRCA2-mutant PCa shows genomic and epigenomic dysregulation of the MED12L/MED12 axis, which is frequently dysregulated in metastatic castration-resistant prostate cancer (mCRPC). This dysregulation is enriched in BRCA2-mutant PCa harbouring intraductal carcinoma (IDC). Microdissection and sequencing of IDC and juxtaposed adjacent non-IDC invasive carcinoma in 10 patients demonstrates a common ancestor to both histopathologies. Overall we show that localized castration-sensitive BRCA2-mutant tumours are uniquely aggressive, due to de novo aberration in genes usually associated with metastatic disease, justifying aggressive initial treatment.
Autism spectrum disorders (ASDs) are neurodevelopmental syndromes characterised by repetitive behaviours and restricted interests, impairments in social behaviour and relations, and in language and ...communication. These symptoms are also observed in a number of developmental disorders of known origin, including Fragile X Syndrome, Rett Syndrome, and Foetal Anticonvulsant Syndrome. While these conditions have diverse etiologies, and poorly understood pathologies, emerging evidence suggests that they may all be linked to dysfunction in particular aspects of GABAergic inhibitory signalling in the brain. We review evidence from genetics, molecular neurobiology and systems neuroscience relating to the role of GABA in these conditions. We conclude by discussing how these deficits may relate to the specific symptoms observed.
There is increasing evidence that children with autism spectrum disorder (ASD) have age-related differences from controls in cortical volume (CV). It is less clear, however, if these persist in ...adulthood and whether these reflect alterations in cortical thickness (CT) or cortical surface area (SA). Hence, we used magnetic resonance imaging to investigate the relationship between age and CV, CT, and SA in 127 males aged 10 through 60 years (76 with ASD and 51 healthy controls). “Regional” analyses (using cortical parcellation) identified significant age-by-group interactions in both CV and CT (but not SA) in the temporal lobes and within these the fusiform and middle temporal gyri. Spatially nonbiased “vertex-based” analysis replicated these results and identified additional “age-by-group” interactions for CT within superior temporal, inferior and medial frontal, and inferior parietal cortices. Here, CV and CT were 1) significantly negatively correlated with age in controls, but not in ASD, and 2) smaller in ASD than controls in childhood but vice versa in adulthood. Our findings suggest that CV dysmaturation in ASD extends beyond childhood, affects brain regions crucial to social cognition and language, and is driven by CT dysmaturation. This may reflect primary abnormalities in cortical plasticity and/or be secondary to disturbed interactions between individuals with ASD and their environment.
Repetitive behaviour and inhibitory control deficits are core features of autism; and it has been suggested that they result from differences in the anatomy of striatum; and/or the ‘connectivity’ of ...subcortical regions to frontal cortex. There are few studies, however, that have measured the micro-structural organisation of white matter tracts connecting striatum and frontal cortex.
To investigate differences in bulk volume of striatum and micro-structural organisation of fronto-striatal white matter in people with autism; and their association with repetitive behaviour and inhibitory control.
We compared the bulk volume of striatum (caudate nucleus, putamen and nucleus accumbens) and white matter organisation of fronto-striatal tracts using (respectively) structural magnetic resonance imaging (sMRI) and tract specific diffusion tensor imaging (DTI) measures in 21 adults with autism and 22 controls. We also assessed performance on a cognitive inhibition (go/nogo) task.
Bulk volume of striatal structures did not differ between groups. However, adults with autism had a significantly smaller total brain white matter volume, lower fractional anisotropy of white matter tracts connecting putamen to frontal cortical areas, higher mean diffusivity of white matter tracts connecting accumbens to frontal cortex and worse performance on the go/nogo task. Also, performance on the go/nogo task was significantly related to anatomical variation when both groups were combined; but not within the autism group alone.
These data suggest that autism may be associated with differences in the anatomy of fronto-striatal white matter tracts.
Neurodevelopmental disorders have a heritable component and are associated with region specific alterations in brain anatomy. However, it is unclear how genetic risks for neurodevelopmental disorders ...are translated into spatially patterned brain vulnerabilities. Here, we integrated cortical neuroimaging data from patients with neurodevelopmental disorders caused by genomic copy number variations (CNVs) and gene expression data from healthy subjects. For each of the six investigated disorders, we show that spatial patterns of cortical anatomy changes in youth are correlated with cortical spatial expression of CNV genes in neurotypical adults. By transforming normative bulk-tissue cortical expression data into cell-type expression maps, we link anatomical change maps in each analysed disorder to specific cell classes as well as the CNV-region genes they express. Our findings reveal organizing principles that regulate the mapping of genetic risks onto regional brain changes in neurogenetic disorders. Our findings will enable screening for candidate molecular mechanisms from readily available neuroimaging data.
Sensory processing abnormalities are common in autism spectrum disorders (ASD), and now form part of the Diagnostic and Statistical Manual 5th Edition (DSM-5) diagnostic criteria, but it is unclear ...whether they characterize the ‘broader phenotype’ of the disorder. We recruited adults (
n
= 772) with and without an ASD and administered the Autism Quotient (AQ) along with the Adult/Adolescent Sensory Profile (AASP), the Cardiff Anomalous Perceptions Scale (CAPS), and the Glasgow Sensory Questionnaire (GSQ), all questionnaire measures of abnormal sensory responsivity. Autism traits were significantly correlated with scores on all three sensory scales (AQ/GSQ
r
= 0.478; AQ/AASP
r
= 0.344; AQ/CAPS
r
= 0.333; all
p
< 0.001). This relationship was linear across the whole range of AQ scores and was true both in those with, and without, an ASD diagnosis. It survived correction for anxiety trait scores, and other potential confounds such as mental illness and migraine.
Autism and mood disorders Oakley, Bethany; Loth, Eva; Murphy, Declan G.
International Review of Psychiatry,
04/2021, Letnik:
33, Številka:
3
Journal Article, Book Review
Recenzirano
Odprti dostop
Individuals with autism experience substantially higher rates of mood problems compared to the general population, which contribute to reduced quality of life and increased mortality through suicide. ...Here, we reviewed evidence for the clinical presentation, aetiology and therapeutic approaches for mood problems in autism. We identified a lack of validated tools for accurately identifying mood problems in individuals with autism, who may present with 'atypical' features (e.g. severe irritability). Risk factors for mood problems in autism appear to be largely overlapping with those identified in the general population, including shared genetic, environmental, cognitive, physiological/neurobiological mechanisms. However, these mechanisms are exacerbated directly/indirectly by lived experiences of autism, including increased vulnerability for chronic stress - often related to social-communication difficulties(/bullying) and sensory sensitivities. Lastly, current therapeutic approaches are based on recommendations for primary mood disorders, with little reference to the neurobiological/cognitive differences associated with autism. Thus, we recommend: 1) the development and validation of (objective) tools to identify mood problems in autism and measure therapeutic efficacy; 2) an interactive approach to investigating aetiologies in large-scale longitudinal studies, integrating different levels of analysis (e.g. cognitive, neurobiological) and lived experience; 3) testing potential treatments through high-quality (e.g. sufficiently powered, blinded) clinical trials, specifically for individuals with autism.
Take Home Message Metastasis-directed therapy is of interest for the management of oligometastatic prostate cancer. Improved imaging may help with patient selection, but the approach to metastatic ...prostate cancer of “catching 'em all”, or “Pokemet”, must be considered experimental.
Rationale
Previous studies on psychotropic drugs prescribing in autism spectrum disorder (ASD) were from the USA or the UK. However, these studies may not be generalizable to other countries. There ...is a need to understand the extent of psychopharmacological prescribing for ASD treatment at a multinational level to identify areas of prescribing which lack evidence.
Methods
We used the IMS Prescribing Insights database to investigate psychotropic drugs prescribing patterns for ASD treatment in children and adults in 2010–2012. Data were obtained from Europe (France, Germany, Italy, Spain and UK), South America (Mexico and Brazil), North America (Canada and USA) and Asia (Japan).
Results
North American countries have the highest prescription rates, followed by the European and South American countries. Prescribing rates were higher in children compared to adults in individual countries. The most commonly prescribed drug for ASD was risperidone in young people (except in UK and Japan). In the UK, methylphenidate (34 %) was the most commonly prescribed for young people and haloperidol (44.1 %) in Japan. In adults, the most commonly prescribed drug class was antipsychotics and particularly risperidone (thioridazine and ziprasidone were the most prescribed antipsychotics in Brazil and USA, respectively).
Conclusion
There is variation in medication prescription for people with ASD among countries, which may be attributable to diagnostic criteria, clinical guidelines or health care systems. However, there is a lack of evidence of efficacy and safety for many psychotropic drugs prescribed for people with ASD. Research is needed to bridge the evidence gaps in prescribing.
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