Auditory N1 event-related potential amplitude is predictive of serum concentration of BPN14770 in fragile x syndrome.

Fragile X syndrome (FXS) is a rare neurodevelopmental disorder caused by a CGG repeat expansion ≥ 200 repeats in 5' untranslated region of the FMR1 gene, leading to intellectual disability and cognitive difficulties, including in the domain of communication. A recent phase 2a clinical trial testing BPN14770, a phosphodiesterase 4D inhibitor, showed improved cognition in 30 adult males with FXS on drug relative to placebo. The initial study found significant improvements in clinical measures assessing cognition, language, and daily functioning in addition to marginal improvements in electroencephalography (EEG) results for the amplitude of the N1 event-related potential (ERP) component. EEG results suggest BPN14770 improved neural hyperexcitability in FXS. The current study investigated the relationship between BPN14770 pharmacokinetics (PK) and the amplitude of the N1 ERP component from the initial data. Consistent with the original group-level finding in period 1 of the study, participants who received BPN14770 in the period 1 showed a significant correlation between N1 amplitude and serum concentration of BPN14770. These findings strengthen the validity of the original result, indicating that BPN14770 improves cognitive performance by modulating neural hyperexcitability. This study represents the first report of significant correlation between a reliably abnormal EEG marker and serum concentration of a novel pharmaceutical in FXS.

The comparison of expressed emotion of parents of individuals with fragile X syndrome to other intellectual disabilities.

BACKGROUND: Parenting children and young adults with intellectual disabilities, including individuals with fragile X syndrome and Down syndrome, is challenging, joyful, and complicated. Exploring how parents talk about their children, and the quality of the parent/child relationship can provide insight into the home environment and interactional patterns of the family. METHOD: Expressed emotion (EE) is a measurement of a family's emotional climate based on a parent or caregiver's report of warmth, emotional overinvolvement, hostility, and criticism. The purpose of this study was to describe EE for a sample of parents of individuals with intellectual disabilities and to determine any differences in EE amongst individuals within subgroups. Based on previous research about fragile X syndrome and family systems, we hypothesized that there would be significant differences between the disability groups (higher EE in families with children/young adults with fragile X syndrome). RESULTS: Results showed relatively high proportions of EE across groups of individuals with intellectual disabilities, however, there were no significant differences between the subgroups. Null findings suggest that differences in EE may not relate directly to a child's specific genetic condition. Rather, increased EE in caregiver populations may simply reflect well-documented stressors related to stigma, caregiver burden, and limited community supports. Critical statements were infrequent, however, over half of the participants reported dissatisfaction with their situation, and many were categorized as having emotional overinvolvement, as measured by frequent statements of intense worry and self-sacrifice. CONCLUSION: Findings point to potential utility in family-level interventions focused on providing structured caregiver therapy to manage excessive worry and grief related to a diagnosis of intellectual disability, and respite care to encourage caregiver independence and pursuit of personal care.

Sensitivity of the NIH Toolbox to Detect Cognitive Change in Individuals With Intellectual and Developmental Disability.

BACKGROUND AND OBJECTIVE: Individuals with intellectual disability (ID) experience protracted cognitive development compared with typical youth. Sensitive measurement of cognitive change in this population is a critical need for clinical trials and other intervention studies, but well-validated outcome measures are scarce. This study's aim was to evaluate the sensitivity of the NIH Toolbox Cognition Battery (NIHTB-CB) to detect developmental changes in groups with ID-fragile X syndrome (FXS), Down syndrome (DS), and other ID (OID)-and to provide further support for its use as an outcome measure for treatment trials. METHODS: We administered the NIHTB-CB and a reference standard cross-validation measure (Stanford-Binet Intelligence Scales, Fifth Edition [SB5]) to 256 individuals with FXS, DS, and OID (ages 6-27 years). After 2 years of development, we retested 197 individuals. Group developmental changes in each cognitive domain of the NIHTB-CB and SB5 were assessed using latent change score models, and 2-year growth was evaluated at 3 age points (10, 16, and 22 years). RESULTS: Overall, effect sizes of growth measured by the NIHTB-CB tests were comparable with or exceeded those of the SB5. The NIHTB-CB showed significant gains in almost all domains in OID at younger ages (10 years), with continued gains at 16 years and stability in early adulthood (22 years). The FXS group showed delayed gains in attention and inhibitory control compared with OID. The DS group had delayed gains in receptive vocabulary compared with OID. Unlike the other groups, DS had significant growth in early adulthood in 2 domains (working memory and attention/inhibitory control). Notably, each group's pattern of NIHTB-CB growth across development corresponded to their respective pattern of SB5 growth. DISCUSSION: The NIHTB-CB is sensitive to developmental changes in individuals with ID. Comparison with levels and timing of growth on the cross-validation measure shows that the NIHTB-CB has potential to identify meaningful trajectories across cognitive domains and ID etiologies. Sensitivity to change within the context of treatment studies and delineation of clinically meaningful changes in NIHTB-CB scores, linked to daily functioning, must be established in future research to evaluate the battery more completely as a key outcome measure.

Assessing processing speed among individuals with intellectual and developmental disabilities: A match-to-sample paradigm.

Speeded Matching (SpM) is a new processing speed match-to-sample test within the NIH Toolbox Cognitive Battery. It was designed to developmentally extend feasibility to younger children or individuals with intellectual or developmental disabilities (IDD). SpM reduces cognitive demands to tapping an identical match as opposed to judging and indicating whether two stimuli are identical. In this study, we piloted SpM among 148 participants with fragile X syndrome, Down syndrome, or other intellectual disabilities (chronological age mean = 17.8 years, sd = 5.4; nonverbal mental age mean = 65 months, sd = 19.4). SpM had a high feasibility (96%) and internal consistency (rxx = 0.98). It converged well with other measures of processing speed, fluid cognition, and nonverbal mental age and diverged appropriately from crystallized cognitive skills. The correlation between nonverbal mental age and SpM in the IDD sample was not significantly different than the correlation between chronological age and SpM in a separate sample of 118 neurotypical children (age mean = 3.9 years sd = 0.8). This study provides initial evidence for the reliability and validity of the new SpM task, which may be appropriate as an outcome measure of processing speed for future clinical trials. It is more feasible than tasks designed for adults; it is brief, easy to administer, and engaging for young children and older individuals with lower mental ages associated with IDD.

A novel measure of matching categories for early development: Item creation and pilot feasibility study.

BACKGROUND: Many cognitive tests assess a limited developmental span, making longitudinal measurement for trials aimed at improving cognition challenging. Tests targeting transitional skills, which integrate foundational abilities into complex schemas, may be amenable to assessment across a wide developmental span. Furthermore, tablet-based tests permit computer adaptive testing (CAT), which is psychometrically more efficient and could increase testing motivation, especially for children with developmental delays. Such measures may be useful for research and clinical practice. AIMS: Outline the creation of a novel, tablet-based concept formation test, and evaluate its feasibility in individuals with mental ages less than 24-months. METHODS AND PROCEDURES: Item generation, user interface construction, and pre-piloting were conducted in consultation with subject matter experts. Item content and interface parameters underwent iterative revisions, resulting in the pilot test. OUTCOMES AND RESULTS: We created and piloted a tablet-based test of concept formation suitable for CAT-based administration with items of increasing difficulty based on target salience. We show feasibility in individuals with mental ages less than 24-months-old. CONCLUSIONS AND IMPLICATIONS: Tablet-based assessment of concept formation may be a useful outcome measure of an aspect of cognitive ability in young children. Future work will address optimizing the user interface and developing CAT administration.

Inhibition of phosphodiesterase-4D in adults with fragile X syndrome: a randomized, placebo-controlled, phase 2 clinical trial.

The goal of this study was to determine whether a phosphodiesterase-4D (PDE4D) allosteric inhibitor (BPN14770) would improve cognitive function and behavioral outcomes in patients with fragile X syndrome (FXS). This phase 2 trial was a 24-week randomized, placebo-controlled, two-way crossover study in 30 adult male patients (age 18-41 years) with FXS. Participants received oral doses of BPN14770 25 mg twice daily or placebo. Primary outcomes were prespecified as safety and tolerability with secondary efficacy outcomes of cognitive performance, caregiver rating scales and physician rating scales (ClinicalTrials.gov identifier: NCT03569631 ). The study met the primary outcome measure since BPN14770 was well tolerated with no meaningful differences between the active and placebo treatment arms. The study also met key secondary efficacy measures of cognition and daily function. Cognitive benefit was demonstrated using the National Institutes of Health Toolbox Cognition Battery assessments of Oral Reading Recognition (least squares mean difference +2.81, P = 0.0157), Picture Vocabulary (+5.81, P = 0.0342) and Cognition Crystallized Composite score (+5.31, P = 0.0018). Benefit as assessed by visual analog caregiver rating scales was judged to be clinically meaningful for language (+14.04, P = 0.0051) and daily functioning (+14.53, P = 0.0017). Results from this study using direct, computer-based assessment of cognitive performance by adult males with FXS indicate significant cognitive improvement in domains related to language with corresponding improvement in caregiver scales rating language and daily functioning.

Validation of the NIH Toolbox Cognitive Battery in intellectual disability.

OBJECTIVE: To advance the science of cognitive outcome measurement for individuals with intellectual disability (ID), we established administration guidelines and evaluated the psychometric properties of the NIH-Toolbox Cognitive Battery (NIHTB-CB) for use in clinical research. METHODS: We assessed feasibility, test-retest reliability, and convergent validity of the NIHTB-CB (measuring executive function, processing speed, memory, and language) by assessing 242 individuals with fragile X syndrome (FXS), Down syndrome (DS), and other ID, ages 6 through 25 years, with retesting completed after 1 month. To facilitate accessibility and measurement accuracy, we developed accommodations and standard assessment guidelines, documented in an e-manual. Finally, we assessed the sensitivity of the battery to expected syndrome-specific cognitive phenotypes. RESULTS: Above a mental age of 5.0 years, all tests had excellent feasibility. More varied feasibility across tests was seen between mental ages of 3 and 4 years. Reliability and convergent validity ranged from moderate to strong. Each test and the Crystallized and Fluid Composite scores correlated moderately to strongly with IQ, and the Crystallized Composite had modest correlations with adaptive behavior. The NIHTB-CB showed known-groups validity by detecting expected executive function deficits in FXS and a receptive language deficit in DS. CONCLUSION: The NIHTB-CB is a reliable and valid test battery for children and young adults with ID with a mental age of ≈5 years and above. Adaptations for very low-functioning or younger children with ID are needed for some subtests to expand the developmental range of the battery. Studies examining sensitivity to developmental and treatment changes are now warranted.