Lonnie Zwaigenbaum

Behavioral manifestations of autism in the first year of life

In the interest of more systematically documenting the early signs of autism, and of testing specific hypotheses regarding their underlying neurodevelopmental substrates, we have initiated a longitudinal study of high‐risk infants, all of whom have an older sibling diagnosed with an autistic spectrum disorder. Our sample currently includes 150 infant siblings, including 65 who have been followed to age 24 months, who are the focus of this paper. We have also followed a comparison group of low‐risk infants. Our measures include a novel observational scale (the first, to our knowledge, that is designed to assess autism‐specific behavior in infants), a computerized visual orienting task, and standardized measures of temperament, cognitive and language development. Our preliminary results indicate that by 12 months of age, siblings who are later diagnosed with autism may be distinguished from other siblings and low‐risk controls on the basis of: (1) several specific behavioral markers, including atypicalities in eye contact, visual tracking, disengagement of visual attention, orienting to name, imitation, social smiling, reactivity, social interest and affect, and sensory‐oriented behaviors; (2) prolonged latency to disengage visual attention; (3) a characteristic pattern of early temperament, with marked passivity and decreased activity level at 6 months, followed by extreme distress reactions, a tendency to fixate on particular objects in the environment, and decreased expression of positive affect by 12 months; and (4) delayed expressive and receptive language. We discuss these findings in the context of various neural networks thought to underlie neurodevelopmental abnormalities in autism, including poor visual orienting. Over time, as we are able to prospectively study larger numbers and to examine interrelationships among both early‐developing behaviors and biological indices of interest, we hope this work will advance current understanding of the neurodevelopmental origins of autism.

Reliability and Accuracy of Differentiating Pervasive Developmental Disorder Subtypes

OBJECTIVE To evaluate the ability of the DSM-IV criteria for the pervasive developmental disorders (PDD) to reliably and accurately differentiate PDD subtypes. METHOD The sample consisted of 143 children with various types of developmental disabilities. A diagnosis of PDD and PDD subtype was made by one clinician using information obtained from the Autism Diagnostic Interview-Revised and the Autism Diagnostic Observation Schedule. The raw data from the Autism Diagnostic Interview-Revised, clinical notes (excluding diagnostic opinion), Autism Diagnostic Observation Schedule, IQ, and other available data were independently assessed by three experienced raters, each of whom then made a separate, blind diagnosis. If there was any disagreement, a consensus best-estimate (CBE) diagnosis was made after discussion. To assess reliability, the agreement between the three raters was calculated using k. Accuracy was assessed by calculating the agreement between the clinicians diagnosis and the CBE and by calculating the error rates associated with the three raters using latent class analysis. RESULTS The current DSM-IV criteria show good to excellent reliability for the diagnosis of PDD, Aspergers disorder (AsD), and autism, but they show poor reliability for the diagnosis of atypical autism. The clinician (compared to the CBE) had little difficulty differentiating PDD from non-PDD children and autism from AsD but had more difficulty identifying children with atypical autism. The latent class analysis also showed that the average error rates of the three raters for a differentiation of atypical autism from autism were unacceptably high. CONCLUSIONS Although the psychometric properties of the current DSM-IV criteria for autism and AsD appear quite acceptable, there is likely to be a high rate of misclassification of children given a diagnosis of atypical autism.

White Matter Microstructure and Atypical Visual Orienting in 7-Month-Olds at Risk for Autism

OBJECTIVE The authors sought to determine whether specific patterns of oculomotor functioning and visual orienting characterize 7-month-old infants who later meet criteria for an autism spectrum disorder (ASD) and to identify the neural correlates of these behaviors. METHOD Data were collected from 97 infants, of whom 16 were high-familial-risk infants later classified as having an ASD, 40 were high-familial-risk infants who did not later meet ASD criteria (high-risk negative), and 41 were low-risk infants. All infants underwent an eye-tracking task at a mean age of 7 months and a clinical assessment at a mean age of 25 months. Diffusion-weighted imaging data were acquired for 84 of the infants at 7 months. Primary outcome measures included average saccadic reaction time in a visually guided saccade procedure and radial diffusivity (an index of white matter organization) in fiber tracts that included corticospinal pathways and the splenium and genu of the corpus callosum. RESULTS Visual orienting latencies were longer in 7-month-old infants who expressed ASD symptoms at 25 months compared with both high-risk negative infants and low-risk infants. Visual orienting latencies were uniquely associated with the microstructural organization of the splenium of the corpus callosum in low-risk infants, but this association was not apparent in infants later classified as having an ASD. CONCLUSIONS Flexibly and efficiently orienting to salient information in the environment is critical for subsequent cognitive and social-cognitive development. Atypical visual orienting may represent an early prodromal feature of an ASD, and abnormal functional specialization of posterior cortical circuits directly informs a novel model of ASD pathogenesis.

The impact of the metabotropic glutamate receptor and other gene family interaction networks on autism

Although multiple reports show that defective genetic networks underlie the aetiology of autism, few have translated into pharmacotherapeutic opportunities. Since drugs compete with endogenous small molecules for protein binding, many successful drugs target large gene families with multiple drug binding sites. Here we search for defective gene family interaction networks (GFINs) in 6,742 patients with the ASDs relative to 12,544 neurologically normal controls, to find potentially druggable genetic targets. We find significant enrichment of structural defects (P≤2.40E−09, 1.8-fold enrichment) in the metabotropic glutamate receptor (GRM) GFIN, previously observed to impact attention deficit hyperactivity disorder (ADHD) and schizophrenia. Also, the MXD-MYC-MAX network of genes, previously implicated in cancer, is significantly enriched (P≤3.83E−23, 2.5-fold enrichment), as is the calmodulin 1 (CALM1) gene interaction network (P≤4.16E−04, 14.4-fold enrichment), which regulates voltage-independent calcium-activated action potentials at the neuronal synapse. We find that multiple defective gene family interactions underlie autism, presenting new translational opportunities to explore for therapeutic interventions.

Increased Extra-axial Cerebrospinal Fluid in High-Risk Infants Who Later Develop Autism

BACKGROUND We previously reported that infants who developed autism spectrum disorder (ASD) had increased cerebrospinal fluid (CSF) in the subarachnoid space (i.e., extra-axial CSF) from 6 to 24 months of age. We attempted to confirm and extend this finding in a larger independent sample. METHODS A longitudinal magnetic resonance imaging study of infants at risk for ASD was carried out on 343 infants, who underwent neuroimaging at 6, 12, and 24 months. Of these infants, 221 were at high risk for ASD because of an older sibling with ASD, and 122 were at low risk with no family history of ASD. A total of 47 infants were diagnosed with ASD at 24 months and were compared with 174 high-risk and 122 low-risk infants without ASD. RESULTS Infants who developed ASD had significantly greater extra-axial CSF volume at 6 months compared with both comparison groups without ASD (18% greater than high-risk infants without ASD; Cohens d = 0.54). Extra-axial CSF volume remained elevated through 24 months (d = 0.46). Infants with more severe autism symptoms had an even greater volume of extra-axial CSF from 6 to 24 months (24% greater at 6 months, d = 0.70; 15% greater at 24 months, d = 0.70). Extra-axial CSF volume at 6 months predicted which high-risk infants would be diagnosed with ASD at 24 months with an overall accuracy of 69% and corresponding 66% sensitivity and 68% specificity, which was fully cross-validated in a separate sample. CONCLUSIONS This study confirms and extends previous findings that increased extra-axial CSF is detectable at 6 months in high-risk infants who develop ASD. Future studies will address whether this anomaly is a contributing factor to the etiology of ASD or an early risk marker for ASD.

Behavioral Pediatrics Feeding Assessment Scale in Young Children With Autism Spectrum Disorder: Psychometrics and Associations With Child and Parent Variables

OBJECTIVE The factor structure and validity of the Behavioral Pediatrics Feeding Assessment Scale (BPFAS; Crist & Napier-Phillips, 2001) were examined in preschoolers with autism spectrum disorder (ASD). METHODS Confirmatory factor analysis was used to examine the original BPFAS five-factor model, the fit of each latent variable, and a rival one-factor model. None of the models was adequate, thus a categorical exploratory factor analysis (CEFA) was conducted. Correlations were used to examine relations between the BPFAS and concurrent variables of interest. RESULTS The CEFA identified an acceptable three-factor model. Correlational analyses indicated that feeding problems were positively related to parent-reported autism symptoms, behavior problems, sleep problems, and parenting stress, but largely unrelated to performance-based indices of autism symptom severity, language, and cognitive abilities, as well as child age. CONCLUSION These results provide evidence supporting the use of the identified BPFAS three-factor model for samples of young children with ASD.

Early expressive and receptive language trajectories in high-risk infant siblings of children with autism spectrum disorder:

Background & aims In response to limited research on early language development in infants at high risk for Autism Spectrum Disorder (ASD), the current prospective study examined early expressive and receptive language trajectories in familial high-risk (HR) infants who were and were not later diagnosed with ASD (HR-ASD and HR-N, respectively), and low-risk (LR) controls with no family history of ASD. Methods Participants were 523 children (371 HR siblings, 56% boys; 152 LR controls, 52% boys) followed from age 6 or 12 months to 36 months. Based on independent, best-estimate clinical diagnoses at 36 months, HR participants were classified as HR-ASD (n = 94; 69% boys), or HR-N (n = 277; 52% boys); the sample also included 152 LR controls (52% boys). Expressive and receptive language trajectories were examined based on corresponding domain standard scores on the Mullen Scales of Early Learning (MSEL) at 6, 12, 24, and 36 months. In the combined sample of HR and LR infants, semi-parametric group-based modeling was used to identify distinct trajectories in MSEL standard scores. Results A 3-group solution provided optimal fit to variation in both expressive and receptive language, with the following patterns of scores: (1) inclining from average to above average, (2) stable-average, and (3) declining from average to well below average. For both expressive and receptive language, membership in these trajectories was related to 3-year diagnostic outcomes. Conclusions Although HR-ASD, HR-N, and LR control infants were in each trajectory group, membership in the declining trajectory (expressive and/or receptive) was associated with an ASD diagnosis. Implications Evidence of declining trajectories in either expressive or receptive language may be a risk marker for ASD in a high-risk sample.