Improving the Prediction of Response to Therapy in Autism

Abstract

Summary: Autism is a heterogeneous disorder involving complex mechanisms and systems occurring at diverse times. Because an individual child with autism may have only a subset of all possible abnormalities at a specific time, it may be challenging to identify beneficial effects of an intervention in double-blind, randomized, controlled trials, which compare the mean responses to treatments. Beneficial effects in a small subset of children may be obscured by the lack of effect in the majority. We review the evidence for several potential model systems of biochemical abnormalities that may contribute to the etiology of autism, we describe potential biomarkers or treatment targets for each of these abnormalities, and we provide illustrative treatment trials using this methodology. Potential model systems include immune over and under reactivity, inflammation, oxidative stress, free fatty acid metabolism, mitochondrial dysfunction, and excitotoxicity. Including potential biomarkers and targeted treatments in clinical trials for autism provides a potential method for limiting the heterogeneity of enrolled subjects, which may improve the power of studies to identify beneficial effects of treatments while also improving the understanding of the disease.

Distinct neural bases of disruptive behavior and autism symptom severity in boys with autism spectrum disorder

“…In brief, the results provide the doubly dissociable evidence that disruptive behavior and autism symptom severity in children and adolescents with ASD have distinct, separable neural bases. Critically, these findings imply that differential treatment should be provided to treat disruptive behavior in ASD and the treatment could aim at improving DMN functions (e.g., [72]), while DMN deactivation may also be tested as a neural predictor or mechanism of behavioral response to treatment [73]. …”

Fragile X Syndrome and Targeted Treatment Trials

“…Although the focus of this book and this chapter is on fragile X syndrome (FXS) and animal models for this disorder leading to targeted treatments, this is a phenomenon that has occurred for many other neurodevelopmental disorders including tuberous sclerosis (de Vries 2010), neurofibromatosis and other disorders of the RAS MEK pathways (Rauen et al 2010), Down syndrome (Rueda et al 2008), Rett syndrome (Maezawa and Jin 2010), and others with a known gene deletion or mutation. Targeted treatment strategies are only just beginning in autism, because it is a heterogeneous disorder with no single gene mutation causing the majority of cases (Bent and Hendren 2010). Most cases of autism involve abnormalities occurring in genes involved with synaptic plasticity, brain connectivity, and/or gamma amino butyric acid (GABA) and glutamate imbalances so that brain function is impaired (Belmonte and Bourgeron 2006; Kelleher and Bear 2008; Pinto et al 2010).…”

Inhibition-Based Biomarkers for Autism Spectrum Disorder

“…Cellular and synaptic findings, while difficult to evaluate in live humans, have led to numerous treatment targets addressing potential underlying mechanisms of ASD. Finding surrogate or indirect ways to evaluate for these abnormalities could drastically improve our ability to stratify people with ASD into subgroups likely to respond to a given treatment [13]. Network-level findings, which can be evaluated in humans of all ages using noninvasive techniques such as EEG, MEG, and MRI, offer a window into the emergent properties of groups of neurons whose individual properties may combine to exacerbate or compensate for one another.…”