The neuropathology of autism: defects of neurogenesis and neuronal migration, and dysplastic changes

Abstract

Autism is characterized by a broad spectrum of clinical manifestations including qualitative impairments in social interactions and communication, and repetitive and stereotyped patterns of behavior. Abnormal acceleration of brain growth in early childhood, signs of slower growth of neurons, and minicolumn developmental abnormalities suggest multiregional alterations. The aim of this study was to detect the patterns of focal qualitative developmental defects and to identify brain regions that are prone to developmental alterations in autism. Formalin-fixed brain hemispheres of 13 autistic (4–60 years of age) and 14 age-matched control subjects were embedded in celloidin and cut into 200-μm-thick coronal sections, which were stained with cresyl violet and used for neuropathological evaluation. Thickening of the subependymal cell layer in two brains and subependymal nodular dysplasia in one brain is indicative of active neurogenesis in two autistic children. Subcortical, periventricular, hippocampal and cerebellar heterotopias detected in the brains of four autistic subjects (31%) reflect abnormal neuronal migration. Multifocal cerebral dysplasia resulted in local distortion of the cytoarchitecture of the neocortex in four brains (31%), of the entorhinal cortex in two brains (15%), of the cornu Ammonis in four brains and of the dentate gyrus in two brains. Cerebellar flocculonodular dysplasia detected in six subjects (46%), focal dysplasia in the vermis in one case, and hypoplasia in one subject indicate local failure of cerebellar development in 62% of autistic subjects. Detection of flocculonodular dysplasia in only one control subject and of a broad spectrum of focal qualitative neuropathological developmental changes in 12 of 13 examined brains of autistic subjects (92%) reflects multiregional dysregulation of neurogenesis, neuronal migration and maturation in autism, which may contribute to the heterogeneity of the clinical phenotype.

Class I histone deacetylase inhibition ameliorates social cognition and cell adhesion molecule plasticity deficits in a rodent model of autism spectrum disorder

“…We also attempted to provide some understanding on the nature of this cognitive phenotype by employing a biological motion paradigm as this has a significant correlation with IQ in human ASD (Rutherford and Troje, 2012). A spatial learning paradigm was employed to account for the consequences of the structural deficits observed in the hippocampus of patients with ASD (Wegiel et al, 2010) as these may contribute to the dorsal stream processing deficits associated with this condition. As a measure of construct validity, we evaluated cell adhesion molecule function, specifically neural cell adhesion molecule (NCAM) polysialylation (PSA) state, as this has previously been implicated in the pathogenesis of ASD (Plioplys et al, 1990;Purcell et al, 2001).…”

Childhood Autism Spectrum Disorder and Epilepsy Co-occurrence: Sub-population Prevalence Variances and Risk Modeling

“…Additionally, black children may have less access to the healthcare system and may therefore be under-diagnosed with ASD [20]. We also surmised that the increasing prevalence of congenital anomalies among white children may contribute to the higher prevalence of ASD in whites, given the possibility of uterine environmental insult [3,11]. In the crude and unadjusted prevalence estimate, black children were less likely to be diagnosed with ASD.…”

“…Methodological changes in clinical diagnoses have seen drastic rises in ASD incidence, namely from 1 in 150 diagnosed children in 2000 to 1 in 68 diagnosed children in 2010 [9]. Furthermore, several studies have suggested that 5% to 46% of individuals diagnosed with ASD have been observed to develop some degree of epilepsy, with the greatest risk of development appearing in adolescence [10][11][12]. Previous research studying ASD revealed that males were more likely to be diagnosed by a ratio of 4:1, a finding that has been comparable to other neurodevelopmental comorbidities such as dyslexia and attention deficit disorder [1,13].…”

“…With respect to symptoms and manifestations, there are similarities between the two conditions, yet no causal relationships between ASD and epilepsy have been established suggesting that ASD may be a contributing cause to epilepsy or vice versa. While previous data have explained the presence of co-occurring ASD and epilepsy, there remains a pressing need for more research [1,4,[10][11][12][13]. Evaluation of studies on the prevalence of epilepsy and ASD illustrates the challenges in obtaining reliable and accurate prevalence in these conditions.…”

“…Evaluation of studies on the prevalence of epilepsy and ASD illustrates the challenges in obtaining reliable and accurate prevalence in these conditions. Preliminary studies on disease origins, overlapping phenotypes, and frequency of comorbidity have provoked increased speculation towards an association between ASD and epilepsy [4,[10][11][12][13][14]. Relative to the general population, epilepsy is more common in children with ASD (prototypical form of a group of pervasive developmental disorders that comprise autism, atypical autism, Asperger syndrome and 'other' pervasive development disorder) [4,[10][11][12][13].…”