Shift from Scarce Neuropathological Findings to Emerging Pattern of Developmental Encephalopathy in Autism Spectrum Disorders

Background: Autism is considered a behavioral disorder. Due to scarcity of brains donated for postmortem studies of ASD and limited number of neuropathological studies this functional definition was not questioned for decades. Tissue deficits delayed testing the hypothesis that behavioral changes are associated with a broad spectrum of structural abnormalities corresponding to developmental encephalopathy with brain region and neuronal network specific patterns of structural and functional changes.

Objectives: The overall goal of three groups of researchers from the Mount Sinai School of Medicine, New York State Institute for Basic Research in Developmental Disabilities and University of Maastricht supported by Autism Speaks/Autism Tissue Program was to (a) overcome tissue limitations by examining 14 brain hemispheres of subjects with idiopathic autism and 14 control subjects, (b) examine cases from 4 to 64 years of age to monitor pattern of changes during lifespan, (c) process the entire hemisphere for complex multiregional study which may reveal global and diverse pathology, (d) preserve serial hemispheric sections for qualitative neuropathological studies and unbiased stereological studies of the number and size of neurons and (f) provide access to these collections of slides for researchers examining dozens of brain structures and their subdivisions.

Methods: Entire hemispheres including cerebellum and brainstem of 14 subjects with idiopathic autism and 14 control subjects were dehydrated, embedded in celloidin, cut into hemispheric 200-µm-thick coronal serial sections and stained with cresyl violet for neuropathological and stereological studies. To compare developmental changes in idiopathic and syndromic autism, the 11 brains of subjects diagnosed with syndromic autism caused by chromosome 15 duplication, 11 diagnosed with idiopathic autism and 11 control subjects were embedded in polyethylene glycol and cut into 50-µm-thick sections for stereological and immunocytochemical studies.

Results: Neuropathological studies revealed in both idiopathic and syndromic autism numerous similarities in type, topography and severity of developmental defects of neuronal migration with ectopias, heterotopias, dysplastic changes and subependymal nodular dysplasia which may contribute to epilepsy. Dysplastic changes of the flocculus might be related to altered gaze control. Reduced size of neuronal soma and nucleus detected in almost all examined cortical and subcortical structures may reflect developmental alterations contributing to autism clinical phenotype. Corpus callosum developmental abnormalities including focal agenesis and diffuse hypoplasia with severe deficit of small, medium size and large axons in all segments connecting prefrontal, premotor, motor, sensory and temporal cortex might be another factor associated with a broad spectrum of autism manifestations.

Conclusions: Studies revealed signs of global developmental encephalopathy in idiopathic and syndromic autism including: (a) abnormal neuronal migration with ectopias and heterotopias, dysplastic changes in the cortex, subcortical structures and cerebellum, (b) reduced size of neurons in almost all examined structures, (c) disruption of long range interhemispheric connectivity with congenital focal CC agenesis and diffuse hypoplasia resulting in a severe deficit of interhemispheric connections in all five CC segments. In general, these studies performed by numerous research groups but on the same material indicate that research driven tissue banking/processing provides powerful alternatives in the study of clinicopathological associations in autism.