Summary Over the past decade, in-vivo MRI studies have provided many invaluable insights into the neural substrates underlying autism spectrum disorder (ASD), which is now known to be associated with ...neurodevelopmental variations in brain anatomy, functioning, and connectivity. These systems-level features of ASD pathology seem to develop differentially across the human lifespan so that the cortical abnormalities that occur in children with ASD differ from those noted at other stages of life. Thus, investigation of the brain in ASD poses particular methodological challenges, which must be addressed to enable the comparison of results across studies. Novel analytical approaches are also being developed to facilitate the translation of findings from the research to the clinical setting. In the future, the insights provided by human neuroimaging studies could contribute to biomarker development for ASD and other neurodevelopmental disorders, and to new approaches to diagnosis and treatment.
Accurate staging of high-risk localised, advanced, and metastatic prostate cancer is becoming increasingly more important in guiding local and systemic treatment. Gallium-68 prostate-specific ...membrane antigen (PSMA) positron emission tomography (PET) has increasingly been utilised globally to assess the local and metastatic burden of prostate cancer, typically in biochemically recurrent or advanced disease. Following our previous meta-analysis, a high-volume series has been reported highlighting the utility of 68Ga-PSMA PET in this setting.
To perform a systematic review and meta-analysis to update reported predictors of positive 68Ga-PSMA PET according to prior therapy and proportion of positivity in various anatomical locations with sensitivity and specificity profiles.
We performed critical reviews of MEDLINE, EMBASE, ScienceDirect, Cochrane Libraries, and Web of Science databases in July 2018 according to the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) statement. Quality assessment was performed using Quality Assessment if Diagnostic Accuracy Studies-2 tool. Meta-analyses of proportions were performed using a random-effect model. Summary sensitivity and specificity values were obtained by fitting bivariate hierarchical regression models.
A total of 37 articles including 4790 patients were analysed. For patients with biochemical recurrence, positive 68Ga-PSMA PET scans increased with higher pre-PET prostate-specific antigen (PSA) levels. For PSA categories 0–0.19, 0.2–0.49, 0.5–0.99, 1–1.99, and ≥2ng/ml, the percentages of positive scans were 33%, 45%, 59%, 75%, and 95%, respectively. No significant differences in positivity were noted between Gleason sums ≤7 and ≥8. Significant differences in positivity after biochemical recurrence in the prostate bed were noted between radical prostatectomy (22%) and radiotherapy (52%) patients. On per-node analysis, high sensitivity (75%) and specificity (99%) were observed.
Ga-68-PSMA PET improves detection of metastases with biochemical recurrence, particularly at low pre-PET PSA levels of >0.2ng/ml (33%) and 0.2–0.5ng/ml (45%). Ga-68-PSMA-PET produces favourable sensitivity and specificity profiles on meta-analysis of pooled data. This analysis highlights different anatomic patterns of metastatic spread according to PSMA PET in the primary and biochemically recurrent settings.
Gallium-68 prostate-specific membrane antigen positron emission tomography is now an established imaging technique that has been developed in response to inadequacies in standard of care imaging modalities to improve the detection of metastatic disease in prostate cancer, particularly in the setting of disease recurrence. To date, this imaging modality in the setting of primary staging is controversial, given the paucity of data. In light of the growing body of evidence, we summarised the data to date to provide clinicians with an overview of this imaging modality.
Gallium-68 prostate-specific membrane antigen positron emission tomography is now an established imaging technique that has been developed in response to inadequacies in standard-of-care imaging modalities to improve the detection of metastatic disease in prostate cancer. In light of the growing body of evidence, we summarised the data to date to provide clinicians with an overview of this imaging modality.
Stroke-induced aphasia is associated with adverse effects on quality of life and the ability to return to work. For patients and clinicians the possibility of relying on valid predictors of recovery ...is an important asset in the clinical management of stroke-related impairment. Age, level of education, type and severity of initial symptoms are established predictors of recovery. However, anatomical predictors are still poorly understood. In this prospective longitudinal study, we intended to assess anatomical predictors of recovery derived from diffusion tractography of the perisylvian language networks. Our study focused on the arcuate fasciculus, a language pathway composed of three segments connecting Wernicke's to Broca's region (i.e. long segment), Wernicke's to Geschwind's region (i.e. posterior segment) and Broca's to Geschwind's region (i.e. anterior segment). In our study we were particularly interested in understanding how lateralization of the arcuate fasciculus impacts on severity of symptoms and their recovery. Sixteen patients (10 males; mean age 60 ± 17 years, range 28-87 years) underwent post stroke language assessment with the Revised Western Aphasia Battery and neuroimaging scanning within a fortnight from symptoms onset. Language assessment was repeated at 6 months. Backward elimination analysis identified a subset of predictor variables (age, sex, lesion size) to be introduced to further regression analyses. A hierarchical regression was conducted with the longitudinal aphasia severity as the dependent variable. The first model included the subset of variables as previously defined. The second model additionally introduced the left and right arcuate fasciculus (separate analysis for each segment). Lesion size was identified as the only independent predictor of longitudinal aphasia severity in the left hemisphere beta = -0.630, t(-3.129), P = 0.011. For the right hemisphere, age beta = -0.678, t(-3.087), P = 0.010 and volume of the long segment of the arcuate fasciculus beta = 0.730, t(2.732), P = 0.020 were predictors of longitudinal aphasia severity. Adding the volume of the right long segment to the first-level model increased the overall predictive power of the model from 28% to 57% F(1,11) = 7.46, P = 0.02. These findings suggest that different predictors of recovery are at play in the left and right hemisphere. The right hemisphere language network seems to be important in aphasia recovery after left hemispheric stroke.
Objective:Neuroimaging studies show structural differences in both cortical and subcortical brain regions in children and adults with autism spectrum disorder (ASD) compared with healthy subjects. ...Findings are inconsistent, however, and it is unclear how differences develop across the lifespan. The authors investigated brain morphometry differences between individuals with ASD and healthy subjects, cross-sectionally across the lifespan, in a large multinational sample from the Enhancing Neuroimaging Genetics Through Meta-Analysis (ENIGMA) ASD working group.Method:The sample comprised 1,571 patients with ASD and 1,651 healthy control subjects (age range, 2–64 years) from 49 participating sites. MRI scans were preprocessed at individual sites with a harmonized protocol based on a validated automated-segmentation software program. Mega-analyses were used to test for case-control differences in subcortical volumes, cortical thickness, and surface area. Development of brain morphometry over the lifespan was modeled using a fractional polynomial approach.Results:The case-control mega-analysis demonstrated that ASD was associated with smaller subcortical volumes of the pallidum, putamen, amygdala, and nucleus accumbens (effect sizes Cohen’s d, 0.13 to –0.13), as well as increased cortical thickness in the frontal cortex and decreased thickness in the temporal cortex (effect sizes, −0.21 to 0.20). Analyses of age effects indicate that the development of cortical thickness is altered in ASD, with the largest differences occurring around adolescence. No age-by-ASD interactions were observed in the subcortical partitions.Conclusions:The ENIGMA ASD working group provides the largest study of brain morphometry differences in ASD to date, using a well-established, validated, publicly available analysis pipeline. ASD patients showed altered morphometry in the cognitive and affective parts of the striatum, frontal cortex, and temporal cortex. Complex developmental trajectories were observed for the different regions, with a developmental peak around adolescence. These findings suggest an interplay in the abnormal development of the striatal, frontal, and temporal regions in ASD across the lifespan.
Right hemisphere dominance for visuospatial attention is characteristic of most humans, but its anatomical basis remains unknown. We report the first evidence in humans for a larger parieto-frontal ...network in the right than left hemisphere, and a significant correlation between the degree of anatomical lateralization and asymmetry of performance on visuospatial tasks. Our results suggest that hemispheric specialization is associated with an unbalanced speed of visuospatial processing.
Flexible behavior is critical for everyday decision-making and has been implicated in restricted, repetitive behaviors (RRB) in autism spectrum disorder (ASD). However, how flexible behavior changes ...developmentally in ASD remains largely unknown. Here, we used a developmental approach and examined flexible behavior on a probabilistic reversal learning task in 572 children, adolescents, and adults (ASD N = 321; typical development TD N = 251). Using computational modeling, we quantified latent variables that index mechanisms underlying perseveration and feedback sensitivity. We then assessed these variables in relation to diagnosis, developmental stage, core autism symptomatology, and associated psychiatric symptoms. Autistic individuals showed on average more perseveration and less feedback sensitivity than TD individuals, and, across cases and controls, older age groups showed more feedback sensitivity than younger age groups. Computational modeling revealed that dominant learning mechanisms underpinning flexible behavior differed across developmental stages and reduced flexible behavior in ASD was driven by less optimal learning on average within each age group. In autistic children, perseverative errors were positively related to anxiety symptoms, and in autistic adults, perseveration (indexed by both task errors and model parameter estimates) was positively related to RRB. These findings provide novel insights into reduced flexible behavior in relation to clinical symptoms in ASD.
Positron emission tomography (PET) of 68Ga-labelled prostate-specific membrane antigen (68Ga-PSMA) is an emerging imaging modality introduced to assess the burden of prostate cancer, typically in ...biochemically recurrent or advanced disease. 68Ga-PSMA PET provides the ability to selectively identify and localize metastatic prostate cancer cells and subsequently change patient management. Owing to its limited history, robust sensitivity and specificity data are not available for 68Ga-PSMA PET–positive scans.
A systematic review and meta-analysis of reported predictors of positive 68Ga-PSMA PET and corresponding sensitivity and specificity profiles.
We performed critical reviews of MEDLINE, EMBASE, ScienceDirect, Cochrane Library, and Web of Science databases in April 2016 according to the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) statement. Quality was assessed using the Quality Assessment if Diagnostic Accuracy Studies-2 tool. Meta-analysis and meta-regression of proportions were performed using a random-effects model with pre-PET prostate-specific antigen (PSA) levels as the dependent variable. Summary sensitivity and specificity values were obtained by fitting bivariate hierarchical regression models.
Sixteen articles involving 1309 patients were analysed. The overall percentage of positive 68Ga-PSMA PET among patients was 40% (95% confidence interval CI 19–64%) for primary staging and 76% (95% CI 66–85%) for biochemical recurrence (BCR). Positive 68Ga-PSMA PET scans for BCR patients increased with pre-PET PSA. For the PSA categories 0–0.2, 0.2–1, 1–2, and >2 ng/ml, 42%, 58%, 76%, and 95% scans, respectively, were positive. Shorter PSA doubling time increased 68Ga-PSMA PET positivity. On per-patient analysis, the summary sensitivity and specificity were both 86%. On per-lesion analysis, the summary sensitivity and specificity were 80% and 97%, respectively.
In the setting of BCR prostate cancer, pre-PET PSA predicts the risk of positive 68Ga-PSMA PET. Pooled data indicate favourable sensitivity and specificity profiles compared to choline-based PET imaging techniques.
Positron emission tomography using 68Ga-labelled prostate-specific membrane antigen is an emerging radiological technique developed to improve the characterisation of metastatic prostate cancer. We summarised the data available to date and found that this new test provides excellent rates of detection of cancer spread in late-stage prostate cancer.
68Ga–Prostate-specific membrane antigen positron emission tomograpy is a novel imaging modality used to assess disease extent in advanced prostate cancer. Our study highlights excellent utility in primary staging for high-risk prostate cancer and secondary staging for biochemical recurrence. The pooled data outline acceptable sensitivity in detecting prostate cancer with low prostate-specific antigen (PSA) levels and PSA doubling times.
Autism spectrum disorder (ASD) is a neurodevelopmental condition with multiple causes, comorbid conditions, and a wide range in the type and severity of symptoms expressed by different individuals. ...This makes the neuroanatomy of autism inherently difficult to describe. Here, we demonstrate how a multiparameter classification approach can be used to characterize the complex and subtle structural pattern of gray matter anatomy implicated in adults with ASD, and to reveal spatially distributed patterns of discriminating regions for a variety of parameters describing brain anatomy. A set of five morphological parameters including volumetric and geometric features at each spatial location on the cortical surface was used to discriminate between people with ASD and controls using a support vector machine (SVM) analytic approach, and to find a spatially distributed pattern of regions with maximal classification weights. On the basis of these patterns, SVM was able to identify individuals with ASD at a sensitivity and specificity of up to 90% and 80%, respectively. However, the ability of individual cortical features to discriminate between groups was highly variable, and the discriminating patterns of regions varied across parameters. The classification was specific to ASD rather than neurodevelopmental conditions in general (e.g., attention deficit hyperactivity disorder). Our results confirm the hypothesis that the neuroanatomy of autism is truly multidimensional, and affects multiple and most likely independent cortical features. The spatial patterns detected using SVM may help further exploration of the specific genetic and neuropathological underpinnings of ASD, and provide new insights into the most likely multifactorial etiology of the condition.
Stereotactic ablative body radiotherapy (SABR) is an emerging treatment option for oligometastatic prostate cancer. However, limited prospective evidence is available.
To determine the safety and ...feasibility of single fraction SABR for patients with oligometastatic prostate cancer. Secondary endpoints were local and distant progression-free survival (LPFS and DPFS), toxicity, quality of life (QoL), and prostate-specific antigen response.
In a prospective clinical trial, patients were screened with computed tomography, bone scan, and sodium fluoride positron emission tomography scan and had one to three oligometastases. Kaplan-Meier methods were used to determine LPFS and DPFS. Toxicity was graded using Common Terminology Criteria for Adverse Event version 4.0. QoL was assessed using European Organization for Research and Treatment of Cancer QLQ-C30 and QLQ-BM22 at 1, 3,12, and 24 mo.
A single fraction of 20-Gy SABR to each lesion.
Between 2013 and 2014, 33 consecutive patients received SABR to a total of 50 oligometastases and were followed for 2 yr. The median age was 70 yr. The Gleason score was ≥8 in 15 patients (45%). Twenty patients had bone only, 12 had node only, and one had mixed disease. SABR was feasible and delivered as planned in 97% of cases. There was one grade 3 adverse event (3.0%, vertebral fracture). No patient died. The 1 and 2-yr LPFS was 97% (95% confidence interval CI: 91–100) and 93% (95% CI: 84–100), and DPFS was 58% (95% CI: 43–77) and 39% (95% CI: 25–60), respectively. In those not on androgen deprivation therapy (ADT; n=22), the 2-yr freedom from ADT was 48%. There was no significant difference from baseline QoL observed. Limitations include small sample size, limited duration of follow-up, and lack of a control arm.
A single SABR session was feasible and associated with low morbidity in this cohort. Over one-third of patients did not progress and were free from ADT at 2-yr. QoL measures were maintained with this treatment strategy.
This clinical trial investigated single treatment stereotactic radiotherapy for low volume advanced prostate cancer. The approach was found to be safe with avoidance of hormone therapy in almost half of the participants at 2 yr.
For patients with one to three oligometastases from prostate cancer, single fraction 20-Gy stereotactic ablative body radiotherapy was both safe and feasible. Local and distant progression-free survival at 2 yr were 93% and 39%, respectively. Quality of life was maintained at baseline levels using this treatment strategy.
There is increasing interest in the use of cannabis and its major non-intoxicating component cannabidiol (CBD) as a treatment for mental health and neurodevelopmental disorders, such as autism ...spectrum disorder (ASD). However, before launching large-scale clinical trials, a better understanding of the effects of CBD on brain would be desirable. Preclinical evidence suggests that one aspect of the polypharmacy of CBD is that it modulates brain excitatory glutamate and inhibitory γ-aminobutyric acid (GABA) levels, including in brain regions linked to ASD, such as the basal ganglia (BG) and the dorsomedial prefrontal cortex (DMPFC). However, differences in glutamate and GABA pathways in ASD mean that the response to CBD in people with and without ASD may be not be the same. To test whether CBD 'shifts' glutamate and GABA levels; and to examine potential differences in this response in ASD, we used magnetic resonance spectroscopy (MRS) to measure glutamate (Glx = glutamate + glutamine) and GABA+ (GABA + macromolecules) levels in 34 healthy men (17 neurotypicals, 17 ASD). Data acquisition commenced 2 h (peak plasma levels) after a single oral dose of 600 mg CBD or placebo. Test sessions were at least 13 days apart. Across groups, CBD increased subcortical, but decreased cortical, Glx. Across regions, CBD increased GABA+ in controls, but decreased GABA+ in ASD; the group difference in change in GABA + in the DMPFC was significant. Thus, CBD modulates glutamate-GABA systems, but prefrontal-GABA systems respond differently in ASD. Our results do not speak to the efficacy of CBD. Future studies should examine the effects of chronic administration on brain and behaviour, and whether acute brain changes predict longer-term response.
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