Proactive and reactive cognitive control and dorsolateral prefrontal cortex dysfunction in first episode schizophrenia.

Cognitive control deficits have been consistently documented in patients with schizophrenia. Recent work in cognitive neuroscience has hypothesized a distinction between two theoretically separable modes of cognitive control-reactive and proactive. However, it remains unclear the extent to which these processes are uniquely associated with dysfunctional neural recruitment in individuals with schizophrenia. This functional magnetic resonance imaging (fMRI) study utilized the color word Stroop task and AX Continuous Performance Task (AX-CPT) to tap reactive and proactive control processes, respectively, in a sample of 54 healthy controls and 43 patients with first episode schizophrenia. Healthy controls demonstrated robust dorsolateral prefrontal, anterior cingulate, and parietal cortex activity on both tasks. In contrast, patients with schizophrenia did not show any significant activation during proactive control, while showing activation similar to control subjects during reactive control. Critically, an interaction analysis showed that the degree to which prefrontal activity was reduced in patients versus controls depended on the type of control process engaged. Controls showed increased dorsolateral prefrontal cortex (DLPFC) and parietal activity in the proactive compared to the reactive control task, whereas patients with schizophrenia did not demonstrate this increase. Additionally, patients' DLPFC activity and performance during proactive control was associated with disorganization symptoms, while no reactive control measures showed this association. Proactive control processes and concomitant dysfunctional recruitment of DLPFC represent robust features of schizophrenia that are also directly associated with symptoms of disorganization

A case of recurrent epilepsy-associated rosette-forming glioneuronal tumor with anaplastic transformation in the absence of therapy.

Rosette-forming glioneuronal tumor (RGNT) most commonly occurs adjacent to the fourth ventricle and therefore rarely presents with epilepsy. Recent reports describe RGNT occurrence in other anatomical locations with considerable morphologic and genetic overlap with the epilepsy-associated dysembryoplastic neuroepithelial tumor (DNET). Examples of RGNT or DNET with anaplastic change are rare, and typically occur in the setting of radiation treatment. We present the case of a 5-year-old girl with seizures, who underwent near total resection of a cystic temporal lobe lesion. Pathology showed morphologic and immunohistochemical features of RGNT, albeit with focally overlapping DNET-like patterns. Resections of residual or recurrent tumor were performed 1 year and 5 years after the initial resection, but no adjuvant radiation or chemotherapy was given. Ten years after the initial resection, surveillance imaging identified new and enhancing nodules, leading to another gross total resection. This specimen showed areas similar to the original tumor, but also high-grade foci with oligodendroglial morphology, increased cellularity, palisading necrosis, microvascular proliferation, and up to 13 mitotic figures per 10 high power fields. Ancillary studies the status by sequencing showed wild-type of the isocitrate dehydrogenase 1 (IDH1), IDH2, and human histone 3.3 (H3F3A) genes, and BRAF studies were negative for mutation or rearrangement. Fluorescence in situ hybridization (FISH) showed codeletion of 1p and 19q limited to the high-grade regions. By immunohistochemistry there was loss of nuclear alpha-thalassemia mental retardation syndrome, X-linked (ATRX) expression only in the high-grade region. Next-generation sequencing showed an fibroblast growth factor receptor receptor 1 (FGFR1) kinase domain internal tandem duplication in three resection specimens. ATRX mutation in the high-grade tumor was confirmed by sequencing which showed a frameshift mutation (p.R1427fs), while the apparent 1p/19q-codeletion by FISH was due to loss of chromosome arm 1p and only partial loss of 19q. Exceptional features of this case include the temporal lobe location, 1p/19q loss by FISH without true whole-arm codeletion, and anaplastic transformation associated with ATRX mutation without radiation or chemotherapy

Clinically Significant Anxiety in Children with Autism Spectrum Disorder and Varied Intellectual Functioning

Objective: To evaluate how distinct presentations of anxiety symptoms and intellectual impairment influence the measurement and estimated rate of clinically significant anxiety in autism spectrum disorder (ASD).Method: The sample included 75 children (ages 9-13 years) with ASD and varied IQ and 52 typically developing (TD) controls and parents. Parents completed anxiety symptom scales and a diagnostic interview, designed to (1) differentiate anxiety and ASD and (2) examine DSM-specified and unspecified ("distinct") anxiety presentations in each child, including fears of change, special interests, idiosyncratic stimuli and social confusion rather than evaluation. Children completed standard intellectual and ASD diagnostic assessments.Results: 69% of those with ASD had clinically-significant anxiety, including 21% DSM-specified anxiety disorders, 17% distinct anxiety, and 31% both. Only 8% of TD children had clinically-significant anxiety, all DSM-specified. DSM-specified anxiety disorders in children with ASD and intellectual impairment (IQ<70) were predominantly specific phobias. DSM-specified anxiety other than specific phobia was significantly less common in children with, versus without, intellectual impairment; this was not the case for distinct anxiety. The sensitivities of anxiety scales were moderate to poor, particularly in cases with intellectual impairment.Conclusions: ASD is associated with more frequent and varied presentations of clinical anxiety, which may align with and differ from the specified anxiety disorders of the DSM. Standard parent report anxiety scales have reduced sensitivity to detect clinical anxiety in ASD, particularly in children with intellectual impairment

Relational memory weakness in autism despite the use of a controlled encoding task

IntroductionRecent work challenged past findings that documented relational memory impairments in autism. Previous studies often relied solely on explicit behavioral responses to assess relational memory integrity, but successful performance on behavioral tasks may rely on other cognitive abilities (e.g., executive functioning) that are impacted in some autistic individuals. Eye-tracking tasks do not require explicit behavioral responses, and, further, eye movements provide an indirect measure of memory. The current study examined whether memory-specific viewing patterns toward scenes differ between autistic and non-autistic individuals.MethodsUsing a long-term memory paradigm that equated for complexity between item and relational memory tasks, participants studied a series of scenes. Following the initial study phase, scenes were re-presented, accompanied by an orienting question that directed participants to attend to either features of an item (i.e., in the item condition) or spatial relationships between items (i.e., in the relational condition) that might be subsequently modified during test. At test, participants viewed scenes that were unchanged (i.e., repeated from study), scenes that underwent an “item” modification (an exemplar switch) or a “relational” modification (a location switch), and scenes that had not been presented before. Eye movements were recorded throughout.ResultsDuring study, there were no significant group differences in viewing directed to regions of scenes that might be manipulated at test, suggesting comparable processing of scene details during encoding. However, there was a group difference in explicit recognition accuracy for scenes that underwent a relational change. Marginal group differences in the expression of memory-based viewing effects during test for relational scenes were consistent with this behavioral outcome, particularly when analyses were limited to scenes recognized correctly with high confidence. Group differences were also evident in correlational analyses that examined the association between study phase viewing and recognition accuracy and between performance on the Picture Sequence Memory Test and recognition accuracy.DiscussionTogether, our findings suggest differences in the integrity of relational memory representations and/or in the relationships between subcomponents of memory in autism

Association of Amygdala Development with Different Forms of Anxiety in Autism Spectrum Disorder

Background: The amygdala is widely implicated in both anxiety and autism spectrum disorder. However, no studies have investigated the relationship between co-occurring anxiety and longitudinal amygdala development in autism. Here, the authors characterize amygdala development across childhood in autistic children with and without traditional DSM forms of anxiety and anxieties distinctly related to autism. Methods: Longitudinal MRI scans were acquired at up to four timepoints for 71 autistic and 55 typically developing (TD) children (∼2.5-12 years, 411 timepoints). Traditional DSM anxiety and anxieties distinctly related to autism were assessed at study Time 4 (∼8-12 years) using a diagnostic interview tailored to autism: The Anxiety Disorders Interview Schedule-IV with the Autism Spectrum Addendum. Mixed effects models were used to test group differences at study Time 1 (3.18 years), Time 4 (11.36 years), and developmental differences (age-by-group interactions) in right and left amygdala volume between autistic children with and without DSM or autism distinct anxieties, and TD. Results: Autistic children with DSM anxiety had significantly larger right amygdala volumes compared to TD at both study Time 1 (5.10% increase) and Time 4 (6.11% increase). Autistic children with autism distinct anxieties had significantly slower right amygdala growth compared to TD, autism-no anxiety, and autism-DSM anxiety groups and smaller right amygdala volumes at Time 4 compared to the autism-no anxiety (-8.13% decrease) and autism-DSM anxiety (-12.05% decrease) groups. Conclusions: Disparate amygdala volumes and developmental trajectories between DSM and autism distinct forms of anxiety suggest different biological underpinnings for these common, co-occurring conditions in autism

PATH-38. ROSETTE-FORMING GLIONEURONAL TUMOR IS DEFINED BY FGFR1 ACTIVATING ALTERATIONS WITH FREQUENT ACCOMPANYING PI3K AND MAPK PATHWAY MUTATIONS

Abstract BACKGROUND Rosette-forming glioneuronal tumor (RGNT) is an uncommon CNS tumor originally described in the fourth ventricle characterized by a low-grade glial neoplasm admixed with a rosette-forming neurocytic component. METHODS We reviewed clinicopathologic features of 42 patients with RGNT. Targeted next-generation sequencing was performed, and genome-wide methylation profiling is underway. RESULTS The 20 male and 22 female patients had a mean age of 25 years (range 3–47) at time of diagnosis. Tumors were located within or adjacent to the lateral ventricle (n=16), fourth ventricle (15), third ventricle (9), and spinal cord (2). All 31 tumors assessed to date contained FGFR1 activating alterations, either in-frame gene fusion, kinase domain tandem duplication, or hotspot missense mutation in the kinase domain (p.N546 or p.K656). While 7 of these 31 tumors harbored FGFR1 alterations as the solitary pathogenic event, 24 contained additional pathogenic alterations within PI3-kinase or MAP kinase pathway genes: 5 with additional PIK3CA and NF1 mutations, 4 with PIK3CA mutation, 3 with PIK3R1 mutation (one of which also contained focal RAF1 amplification), 5 with PTPN11 mutation (one with additional PIK3R1 mutation), and 2 with NF1 deletion. The other 5 cases demonstrated anaplastic features including hypercellularity and increased mitotic activity. Among these anaplastic cases, 3 harbored inactivating ATRX mutations and two harbored CDKN2A homozygous deletion, in addition to the FGFR1 alterations plus other PI3-kinase and MAP kinase gene mutations seen in those RGNT without anaplasia. CONCLUSION Independent of ventricular location, RGNT is defined by FGFR1 activating mutations or rearrangements, which are frequently accompanied by mutations involving PIK3CA, PIK3R1, PTPN11, NF1, and KRAS. Whereas pilocytic astrocytoma and ganglioglioma are characterized by solitary activating MAP kinase pathway alterations (e.g. BRAF fusion or mutation), RGNT are genetically more complex with dual PI3K-Akt-mTOR and Ras-Raf-MAPK pathway activation. Rare anaplastic examples may show additional ATRX and/or CDKN2A inactivation

Predicting Friendship Quality in Autism Spectrum Disorders and Typical Development

The role played by social relationship variables (attachment security; mother–child relationship qualities) and social-cognitive capacities (theory of mind) was examined in both observed friendship behaviors and in children’s descriptions of friendships (age 8–12) with high functioning children with autism spectrum disorders (HFASD) (n = 44) and with typical development (TYP) (n = 38). Overall, half of the HFASD sample (54.45%) reported maternal attachment security, corroborating data from younger children with ASD. The hypothesized predictors and their interrelations had both direct and indirect effects on friendship for both groups of children, highlighting the importance of these factors in children’s friendship development and suggesting both compensatory and amplification mechanisms for friendship qualities. Practical and clinical implications are discussed for friendship support in both ASD and TYP

Autism Symptoms and Internalizing Psychopathology in Girls and Boys with Autism Spectrum Disorders

Findings regarding phenotypic differences between boys and girls with ASD are mixed. We compared autism and internalizing symptoms in a sample of 8-18 year-old girls (n = 20) and boys (n = 20) with ASD and typically developing (TYP) girls (n = 19) and boys (n = 17). Girls with ASD were more impaired than TYP girls but did not differ from boys with ASD in autism symptoms. In adolescence, girls with ASD had higher internalizing symptoms than boys with ASD and TYP girls, and higher symptoms of depression than TYP girls. Girls ages 8-18 with ASD resemble boys with ASD and not TYP girls, and appear to be at increased risk for affective symptoms in the teen years

Circulating 25-Hydroxyvitamin D and the Risk of Rarer Cancers: Design and Methods of the Cohort Consortium Vitamin D Pooling Project of Rarer Cancers

The Cohort Consortium Vitamin D Pooling Project of Rarer Cancers (VDPP), a consortium of 10 prospective cohort studies from the United States, Finland, and China, was formed to examine the associations between circulating 25-hydroxyvitamin D (25(OH)D) concentrations and the risk of rarer cancers. Cases (total n = 5,491) included incident primary endometrial (n = 830), kidney (n = 775), ovarian (n = 516), pancreatic (n = 952), and upper gastrointestinal tract (n = 1,065) cancers and non-Hodgkin lymphoma (n = 1,353) diagnosed in the participating cohorts. At least 1 control was matched to each case on age, date of blood collection (1974–2006), sex, and race/ethnicity (n = 6,714). Covariate data were obtained from each cohort in a standardized manner. The majority of the serum or plasma samples were assayed in a central laboratory using a direct, competitive chemiluminescence immunoassay on the DiaSorin LIAISON platform (DiaSorin, Inc., Stillwater, Minnesota). Masked quality control samples included serum standards from the US National Institute of Standards and Technology. Conditional logistic regression analyses were conducted using clinically defined cutpoints, with 50–<75 nmol/L as the reference category. Meta-analyses were also conducted using inverse-variance weights in random-effects models. This consortium approach permits estimation of the association between 25(OH)D and several rarer cancers with high accuracy and precision across a wide range of 25(OH)D concentrations

Is Emotion Recognition Impaired in Individuals with Autism Spectrum Disorders?

Researchers have argued that individuals with autism spectrum disorders (ASDs) use an effortful “systematizing” process to recognize emotion expressions, whereas typically developing (TD) individuals use a more holistic process. If this is the case, individuals with ASDs should show slower and less efficient emotion recognition, particularly for socially complex emotions. We tested this account by assessing the speed and accuracy of emotion recognition while limiting exposure time and response window. Children and adolescents with ASDs showed quick and accurate recognition for most emotions, including pride, a socially complex emotion, and no differences emerged between ASD and TD groups. Furthermore, both groups trended toward higher accuracy when responding quickly, even though systematizing should promote a speed-accuracy trade-off for individuals with ASDs