Structural correlates of functional deficits in Autism Spectrum Disorder

Background: Etiological diversity with genetic, pre-, peri-, and postnatal pathological factors and concurrent diseases contribute to interindividual clinical and neuropathological differences. While genetic and clinical studies of autism are based on examination of thousands of patients and siblings, the search for morphological and molecular equivalents of genetic and clinical abnormalities is limited to about forty brains.

Objectives: Designing of postmortem studies to detect markers of developmental abnormalities corresponding to (a) impairments in reciprocal social interactions, (b) impairments in verbal and nonverbal communication, (c) restricted repetitive and stereotyped patterns of behavior and (c) mental retardation, (d) causes and effects of epilepsy, (e) sudden and unexpected death.

Methods: Future application of same protocols of postmortem MRI, neuropathological studies, unbiased stereological methods, immunocytochemistry and biochemistry will identify differences between patterns of developmental and aging-associated changes in (a) low and (b) high functioning subjects with autism and people diagnosed with (c) Asperger's syndrome and (d) chromosome 15 duplication.

Conclusions: Current studies revealed pivotal role of (a) expanded protocol of neuropathological screening to improve inclusion/exclusion criteria, (b) postmortem quantitative MRI and 3-D reconstruction to monitor changes in size of the brain and brain subdivisions, (c) stereological methods to detect brain structure specific dynamics of developmental changes of size of neuron and neuronal nucleus and patterns of aging associated pathology, (d) immunocytochemistry to characterize metabolic shift resulting in enhanced activity of lysosomal pathways and intracellular deposition of amino-terminally truncated Aβ, and (e) electron microscopy to identify ultrastructural equivalents of pathological changes.