ABSTRACT
Migration Disturbances .....................................................................8 1.4.2 Brain Structure-Speci c Delay of Neuronal Growth .......................9 1.4.3 Minicolumnar Abnormalities in Autism ......................................... 10
1.5 Neuronal Oxidative Stress and Metabolic Changes...................................... 10 1.5.1 Oxidative Stress in Autism .............................................................. 10 1.5.2 Lipofuscin in Autism ....................................................................... 11 1.5.3 β-Amyloid Precursor Protein and Intraneuronal
Amyloid β in Autism .......................................................................12 1.6 Clinicopathological Correlations .................................................................. 13
1.6.1 Speech, Language, and Verbal and Nonverbal Communication ................................................................................ 13
1.6.2 Face Perception ................................................................................ 13 1.6.3 Social Attachment-The Role of the Hypothalamus
in Behavioral De cits ...................................................................... 14 1.6.4 Sensorimotor De cits, and Repetitive
and Stereotyped Behaviors .............................................................. 15 1.6.5 Cognitive De cits............................................................................. 17 1.6.6 Epilepsy-Associated Pathology ........................................................ 17
1.7 Mechanisms Affecting Brain Development .................................................. 18 1.7.1 BDNF and Neurotrophins in Autism ............................................... 18 1.7.2 Brain Stem and the Role of Serotonin in Brain
Development and Clinical Features of Autism ................................ 19 1.8 Closing Remarks .............................................................................................20 Acknowledgments ....................................................................................................20 References ................................................................................................................ 21
The aim of this chapter is to identify the type, topography, and sequelae of neuropathological changes that contribute to the clinical phenotype of autism. Results of recent magnetic resonance imaging (MRI) and postmortem neuropathological and stereological studies of autism brain suggest a dynamic model of sequential subdivision of age-and brain-speci c structural and functional changes. Acceleration of brain growth in the rst year of life and deceleration in the second and third years appear to play a pivotal role in the onset of clinical signs of autism (Courchesne and Pierce, 2005b; Courchesne et al., 2001, 2003; Dawson et al., 2007; Dementieva et al., 2005; Gillberg and de Souza, 2002; Redcay and Courchesne, 2005). The range of deviation from the normal trajectory of brain growth may be a factor determining the severity of the disease (Courchesne et al., 2003). Developmental heterochronicity (differential rates of growth of various brain regions compared to controls), resulting in selective overgrowth of some brain
regions, appears to be a key factor determining topography and brain regionspeci c type of cytoarchitectonic changes (Carper and Courchesne, 2005; Carper et al., 2002; Courchesne et al., 2001; Hazlett et al., 2005; Sparks et al., 2002). Topographic developmental heterochronicity may result in impairment of both local and global connectivity, leading to local overconnectivity and impairment of long-distance connectivity (Baron-Cohen, 2004; Casanova et al., 2006; Courchesne and Pierce, 2005a). Stereological studies have revealed neuronal developmental heterochronicity in early childhood, resulting in selective developmental delay of the growth of neurons in some subcortical structures and the cerebellum during the most critical stage of development of social behaviors and communication skills (Wegiel et al., 2008). Distortions of brain and neuronal development are re ected in abnormal cortical minicolumn organization (Casanova et al., 2002, 2006), local dysgenesis, and ectopias (Bauman and Kemper, 1985; Bauman et al., 1997; Kemper and Bauman, 1993, 1998). These complex developmental abnormalities appear to lay the foundation for secondary and tertiary metabolic, structural, and functional changes, including seizures and risk of sudden unexpected death; signs of oxidative stress, early and enhanced accumulation of products of cell organelle degradation with lipofuscin deposition; modi ed processing of β-amyloid precursor protein with accumulation of truncated amyloid beta; and other as of yet unidenti ed changes. Secondary pathologic changes appear to be indicators of the susceptibility of abnormally developing neurons to further modi cations during cell maturation and aging. The pattern of morphological changes emerging from these multidisciplinary studies appears to represent a major trend. However, modi cations of the course of disease and subpatterns of developmental changes result in a broad spectrum of morphological and clinical interindividual differences.
