Neural correlates of face processing associated with development of social communication in 12-month infants with familial risk of autism spectrum disorder

Background Differences in face processing in individuals with ASD is hypothesized to impact the development of social communication skills. This study aimed to characterize the neural correlates of face processing in 12-month-old infants at familial risk of developing ASD by (1) comparing face-sensitive event-related potentials (ERP) (Nc, N290, P400) between high-familial-risk infants who develop ASD (HR-ASD), high-familial-risk infants without ASD (HR-NoASD), and low-familial-risk infants (LR), and (2) evaluating how face-sensitive ERP components are associated with development of social communication skills. Methods 12-month-old infants participated in a study in which they were presented with alternating images of their mother’s face and the face of a stranger (LR = 45, HR-NoASD = 41, HR-ASD = 24) as EEG data were collected. Parent-reported and laboratory-observed social communication measures were obtained at 12 and 18 months. Group differences in ERP responses were evaluated using ANOVA, and multiple linear regressions were conducted with maternal education and outcome groups as covariates to assess relationships between ERP and behavioral measures. Results For each of the ERP components (Nc [negative-central], N290, and P400), the amplitude difference between mother and stranger (Mother-Stranger) trials was not statistically different between the three outcome groups (Nc p = 0.72, N290 p = 0.88, P400 p = 0.91). Marginal effects analyses found that within the LR group, a greater Nc Mother-Stranger response was associated with better expressive language skills on the Mullen Scales of Early Learning, controlling for maternal education and outcome group effects (marginal effects dy/dx = 1.15; p < 0.01). No significant associations were observed between the Nc and language or social measures in HR-NoASD or HR-ASD groups. In contrast, specific to the HR-ASD group, amplitude difference between the Mother versus Stranger P400 response was positively associated with expressive (dy/dx = 2.1, p < 0.001) and receptive language skills at 12 months (dy/dx = 1.68, p < 0.005), and negatively associated with social affect scores on the Autism Diagnostic Observation Schedule (dy/dx = − 1.22, p < 0.001) at 18 months. Conclusions In 12-month-old infant siblings with subsequent ASD, increased P400 response to Mother over Stranger faces is positively associated with concurrent language and future social skills.

Neurocognition and its association with adverse childhood experiences and familial risk of mental illness

Background: Neurocognitive deficits are considered an endophenotype for several psychiatric disorders, typically studied in unaffected first-degree relatives (FDRs). Environmental factors such as adverse childhood experiences (ACEs) may also affect neurocognition. This study examines the effect of ACEs on neurocognitive performance in FDRs of patients with severe mental illness in order to determine whether familial risk has a moderating effect on the relationship between ACEs and neurocognition. Methods: The sample consists of a total of 512 individuals composed of unaffected FDRs from multiplex families with severe mental illnesses (schizophrenia, bipolar disorder, obsessive-compulsive disorder or alcohol use disorder) and healthy controls (with no familial risk). Neurocognitive tests included processing speed (Color Trails), new learning (Auditory Verbal Learning Test), working memory (N-Back), and Theory of Mind (SOCRATIS). ACEs were measured using the WHO ACE-International Questionnaire (ACE-IQ). Regression models adjusted for age, gender and education were done to predict each neurocognitive domain by the effect of familial risk, ACE-IQ Total Score and the interaction (familial risk x ACE-IQ Total score). Results: When all FDRs were examined as a group, the main effect of familial risk predicted poor performance in all domains of neurocognition (p <0.01), and the ACEs x familial risk interaction had a significant negative association with global neurocognition, processing speed & working memory. This interaction effect was driven predominantly by the familial risk of AUD. In FDRs of schizophrenia & bipolar disorder, only the main effects of familial risk were significant (working memory, theory of mind & global neurocognition), with no impact of ACEs or its interaction in both these sub-groups. Conclusions: The impact of childhood adversity on neurocognition is moderated by familial risk of psychiatric disorders. Genetic or familial vulnerability may play a greater role in disorders such as schizophrenia and bipolar disorder, while the interaction between ACEs and family history may be more relevant in the case of disorders with greater environmental risk, such as substance use.

Neural Correlates of Infant Face Processing and Later Emerging Autism Symptoms in Fragile X Syndrome

Fragile X syndrome (FXS) is the leading known genetic cause of autism spectrum disorder (ASD) with 60–74% of males with FXS meeting diagnostic criteria for ASD. Infants with FXS have demonstrated atypical neural responses during face processing that are unique from both typically developing, low-risk infants and infants at high familial risk for ASD (i.e., infants siblings of children with ASD). In the current study, event-related potential (ERP) responses during face processing measured at 12 months of age were examined in relation to ASD symptoms measured at ~48 months of age in participants with FXS, as well as siblings of children with ASD and low-risk control participants. Results revealed that greater amplitude N290 responses in infancy were associated with more severe ASD symptoms in childhood in FXS and in siblings of children with ASD. This pattern of results was not observed for low-risk control participants. Reduced Nc amplitude was associated with more severe ASD symptoms in participants with FXS but was not observed in the other groups. This is the first study to examine ASD symptoms in childhood in relation to infant ERP responses in FXS. Results indicate that infant ERP responses may be predictive of later symptoms of ASD in FXS and the presence of both common and unique pathways to ASD in etiologically-distinct high-risk groups is supported (i.e., syndromic risk vs. familial risk).

Genome sequencing in the Parkinson disease clinic

Background and Objectives: Genetic variants impact both Parkinson disease (PD) risk and manifestations. While genetic information is of potential interest to patients and clinicians, genetic testing is rarely performed during routine PD clinical care. The goal of this study was to perform genome sequencing and examine patient interest in comprehensive genetic testing for PD in 2 academic movement disorder clinics. Methods: In 208 subjects with PD (age=63 years, 67% male), genome sequencing was performed and filtered using a custom panel, including 49 genes associated with PD, parkinsonism, or related disorders, as well as a 90-variant PD genetic risk score. Separately, 231 patients (age=67 years, 63% male) were surveyed on interest in genetic testing at baseline and in response to vignettes covering (i) familial risk of PD (LRRK2); (ii) risk of PD dementia (GBA); (iii) PD genetic risk score; and (iv) secondary, medically-actionable variants (BRCA1). Results: Genome sequencing revealed a LRRK2 variant in 3.4% and a GBA risk variant in 10.1% of our clinical sample. The genetic risk score was normally distributed, identifying 42 subjects with high risk of PD. Medically-actionable findings were discovered in 2 subjects (1%). In our survey, the majority (82%) responded they would share a LRRK2 variant with relatives. Most registered unchanged or increased interest in testing when confronted with potential risk for dementia or medically- actionable findings, and most (75%) expressed interest in learning their PD genetic risk score. Discussion: Our results highlight broad interest in comprehensive genetic testing among patients with PD and may facilitate integration of genome sequencing in clinical practice.