Impact of trametinib on the neuropsychological profile of NF1 patients.

PURPOSE: The use of trametinib in the treatment of pediatric low-grade gliomas (PLGG) and plexiform neurofibroma (PN) is being investigated in an ongoing multicenter phase II trial (NCT03363217). Preliminary data shows potential benefits with significant response in the majority of PLGG and PN and an overall good tolerance. Moreover, possible benefits of MEK inhibitor therapy on cognitive functioning in neurofibromatosis type 1 (NF1) were recently shown which supports the need for further evaluation. METHODS: Thirty-six patients with NF1 (age range 3-19 years) enrolled in the phase II study of trametinib underwent a neurocognitive assessment at inclusion and at completion of the 72-week treatment. Age-appropriate Wechsler Intelligence Scales and the Trail Making Test (for children over 8 years old) were administered at each assessment. Paired t-tests and Reliable Change Index (RCI) analyses were performed to investigate change in neurocognitive outcomes. Regression analyses were used to investigate the contribution of age and baseline score in the prediction of change. RESULTS: Stable performance on neurocognitive tests was revealed at a group-level using paired t-tests. Clinically significant improvements were however found on specific indexes of the Wechsler intelligence scales and Trail Making Test, using RCI analyses. No significant impact of age on cognitive change was evidenced. However, lower initial cognitive performance was associated with increased odds of presenting clinically significant improvements on neurocognitive outcomes. CONCLUSION: These preliminary results show a potential positive effect of trametinib on cognition in patients with NF1. We observed significant improvements in processing speed, visuo-motor and verbal abilities. This study demonstrates the importance of including neuropsychological evaluations into clinical trial when using MEK inhibitors for patients with NF1.

Prioritizing Solutions and Improving Resources among Young Pediatric Brain Tumor Survivors: Results of an Online Survey.

Pediatric Brain Tumor Survivors (PBTS) often experience social, academic and employment difficulties during aftercare. Despite their needs, they often do not use the services available to them. Following a previous qualitative study, we formulated solutions to help support PBTS return to daily activities after treatment completion. The present study aims to confirm and prioritize these solutions with a larger sample. We used a mixed-methods survey with 68 participants (43 survivors, 25 parents, PBTS' age: 15-39 years). Firstly, we collected information about health condition, and school/work experience in aftercare. Then, we asked participants to prioritize the previously identified solutions using Likert scales and open-ended questions. We used descriptive and inferential statistics to analyze data, and qualitative information to support participants' responses. Participants prioritized the need for evaluation, counseling, and follow-up by health professionals to better understand their post-treatment needs, obtain help to access adapted services, and receive information about resources at school/work. Responses to open-ended questions highlighted major challenges regarding the implementation of professionals' recommendations at school/work and the need for timely interventions. These results will help refine solutions for PBTS and provide key elements for future implementation. Translating these priorities into action will need further work involving professionals and decision makers.

Social cognitive markers of short-term clinical outcome in first-episode psychosis.

OBJECTIVE: In psychotic disorders, impairments in cognition have been associated with both clinical and functional outcome, while deficits in social cognition have been associated with functional outcome. As an extension to a recent report on neurocognition and short-term clinical outcome in first-episode psychosis (FEP), the current study explored whether social cognitive deficits could also identify poor short-term clinical outcome among FEP patients. METHODS: We defined the social-cognition domain based on the scores from the Hinting Task and the Four Factor Tests of Social Intelligence. Data were collected in 45 FEP patients and 26 healthy controls. The patients were divided into good- and poor-outcome groups based on clinical data at six months following initiation of treatment. Social cognition was compared among 27 poor-outcome, 18 good-outcome, and 26 healthy-control participants. RESULTS: Outcome groups significantly differed in the social cognition domain (z-scores: poor outcome=-2.0 [SD=1.4]; good outcome=-1.0 [SD=1.0]; p=0.005), with both groups scoring significantly lower than the control group (p<0.003). Moreover, outcome groups differed significantly only on the Cartoon Predictions subtest (z-scores: poor outcome=-2.7 [SD=2.7]; good outcome=-0.7 [SD=1.8]; p=0.001) among the five subtests used. CONCLUSIONS: Overall, social cognition appears to be compromised in all FEP patients compared to healthy controls. More interestingly, significant differences in social cognitive impairments exist between good and poor short-term clinical outcome groups, with the largest effect found in the Cartoon Predictions subtest.

Structural neural correlates of impairments in social cognition in first episode psychosis.

Several studies have demonstrated that patients with schizophrenia show impairments in social cognition and current evidence indicate that this deficit is associated with abnormal activity in specific brain regions. In addition to functional imaging studies, we believe that the identification of structural correlates of social cognitive processes may help to better understand the neural underpinnings of these specific skills. The main objective of this study was to investigate the relationship between gray matter density and social cognitive deficits in first episode of schizophrenia spectrum psychosis, using a comprehensive assessment that we previously demonstrated to be a highly sensitive measure of social cognitive deficits in this population. Thirty-eight patients with a first episode of psychosis participated in this study, and the Four Factor Test of Social Intelligence was used as a measure of social cognition. Social cognitive impairments in first episode psychosis were significantly correlated with reduced gray-matter density in the left middle frontal gyrus other regions within the mirror neuron system network (MSN), namely the right supplementary motor cortex, the left superior temporal gyrus and the left inferior parietal lobule. We concluded that structural abnormalities within the MSN may account for the social cognitive deficits present in some psychiatric disorders, such as schizophrenia.

Cognitive insight and verbal memory in first episode of psychosis.

Beck and collaborators have proposed a distinction between clinical insight and cognitive insight and have developed a tool for the assessment of the latter, namely the Beck Cognitive Insight Scale (BCIS). The present study explored in 51 patients with a first episode of psychosis the neurocognitive correlates of cognitive insight as assessed with the BCIS. Global measures for seven domains of cognition including verbal learning and memory, visual learning and memory, working memory, speed of processing, reasoning and problem solving, attention, and social cognition were examined. Secondly, we examined whether two clinical insight measures, the Scale to assess Unawareness of Mental Disorder (SUMD) and the insight item from the Positive and Negative Symptoms Scale (PANSS), could produce similar or different patterns of association with neurocognitive functions as those identified with the BCIS. Correlational analyses revealed significant associations between the BCIS Composite Index and the verbal learning and memory. No significant associations were observed between any of the neurocognitive domains and the PANSS or SUMD clinical insight measures, despite high inter-correlations among the three insight measures. These results suggest that cognitive insight, but not clinical insight, may rely on memory processes whereby current experiences are appraised based on previous ones.

Selective abnormal modulation of hippocampal activity during memory formation in first-episode psychosis.

CONTEXT: Memory is one of the cognitive functions most affected in schizophrenia, with deficits observed from the first episode of psychosis (FEP). Previous studies have indicated that some memory processes may be more affected than others. OBJECTIVE: To examine the neural correlates of 3 specific memory processes in FEP by means of functional magnetic resonance imaging (fMRI). DESIGN: Case-control study. SETTING: Prevention and Early Intervention Program for Psychoses of the Douglas Hospital and Montreal Neurological Institute, McGill University. Subjects Twenty-six patients with FEP and 20 healthy controls. MAIN OUTCOME MEASURES: Behavioral performance and regional brain activity measured during memory encoding by fMRI. Our fMRI design included 3 within-subject contrasts (associative vs item-oriented encoding, encoding of arbitrary vs semantically related image pairs, and successful vs unsuccessful memory encoding) that were then used for group conjunctions and between-group analyses. RESULTS: Patients with FEP showed normal activation of several brain regions, including the prefrontal cortex, hippocampus, and parahippocampal cortex, during successful memory encoding and associative encoding. In contrast, the hippocampus and surrounding medial temporal areas showed reduced activity during the encoding of arbitrary pairs. This selective dysfunction reflected by abnormal brain activation during encoding was accompanied by a greater deficit for subsequent recognition of arbitrary pairs relative to the semantically related pairs. CONCLUSIONS: This study demonstrated that, in the same group of patients with FEP, the hippocampus could show either normal or abnormal modulation of activation depending on the specific cognitive process that was examined. The normal modulation of hippocampal activation observed during successful memory encoding in FEP argues against a general inability to recruit this region. Instead, the dysfunction was specifically linked to semantic relatedness. This selective deficit seems to affect memory performance in FEP and denotes an important representational problem that may confer greater vulnerability to psychotic disorders and would thus be interesting to examine in high-risk populations.

Social cognitive impairments in first episode psychosis.

BACKGROUND: Social cognition is a complex phenomenon involving several distinct processes. Numerous studies have shown that individuals with schizophrenia are largely impaired on this domain of cognition. However, most have focused on a single aspect of social cognition, namely "theory of mind" and/or included patients with long standing illness. OBJECTIVE: The main objective of the present study was to identify social cognition deficits in first episode of schizophrenia spectrum psychosis using a case control design and a comprehensive assessment that allowed the exploration of several dimensions of this phenomenon. SUBJECTS: 36 patients with a first episode of psychosis and 25 healthy controls participated in this study. MATERIAL: Measures of social cognition included the Hinting Task and the Four Factor Test of Social Intelligence. RESULTS: Significant group differences were found on both tasks, but the Four Factor Test of Social Intelligence revealed a stronger group effect and the effects observed remained significant once IQ was covaried. Social cognition did not show any correlations with level of symptoms. CONCLUSION: Social cognition deficits are present during the first episode of psychosis. These impairments do not seem to be a consequence of group differences in overall intellectual functioning and are likely to be state-independent.

Medial temporal lobe activations during associative memory encoding for arbitrary and semantically related object pairs.

Previous positron emission tomography (PET) studies have shown greater medial temporal lobe activation (MTL) for associative memory encoding relative to deep item-oriented encoding. Greater MTL activation has also been reported for associative novelty detection. Although it has been suggested that these patterns of MTL activation could reflect the creation of novel associations into memory, it is unclear whether associative encoding and associative novelty detection rely on the same MTL substructures. In this study, we used event-related functional magnetic resonance imaging (er-fMRI) to reproduce previous reports of greater hippocampal activation for associative encoding using both arbitrary and semantically related object pairs. This paradigm allowed us to assess whether the requirement for associative processing at encoding interacts with associative novelty. Contrasting the pattern of activation for associative versus item-oriented encoding revealed greater right hippocampal activation as well as parahippocampal activation bilaterally, reproducing the findings from previous PET experiments. The orthogonal contrast between arbitrary and related pairs revealed greater activation in the left parahippocampal region, but no significant interaction between the type of encoding (associative or item oriented) and the type of pairs (arbitrary or semantically related) was observed in the medial temporal lobe (MTL). These results suggest that both associative processing and associative novelty detection can activate the MTL. Most importantly, this study suggests that associative processing can activate the MTL regardless of the pre-existence of an association between the items of a pair.