Elsevier

Brain Research

Volume 1380, 22 March 2011, Pages 138-145
Brain Research

Research Report
Brain growth across the life span in autism: Age-specific changes in anatomical pathology

https://doi.org/10.1016/j.brainres.2010.09.101Get rights and content

Abstract

Autism is marked by overgrowth of the brain at the earliest ages but not at older ages when decreases in structural volumes and neuron numbers are observed instead. This has led to the theory of age-specific anatomic abnormalities in autism. Here we report age-related changes in brain size in autistic and typical subjects from 12 months to 50 years of age based on analyses of 586 longitudinal and cross-sectional MRI scans. This dataset is several times larger than the largest autism study to date. Results demonstrate early brain overgrowth during infancy and the toddler years in autistic boys and girls, followed by an accelerated rate of decline in size and perhaps degeneration from adolescence to late middle age in this disorder. We theorize that underlying these age-specific changes in anatomic abnormalities in autism, there may also be age-specific changes in gene expression, molecular, synaptic, cellular, and circuit abnormalities. A peak age for detecting and studying the earliest fundamental biological underpinnings of autism is prenatal life and the first three postnatal years. Studies of the older autistic brain may not address original causes but are essential to discovering how best to help the older aging autistic person. Lastly, the theory of age-specific anatomic abnormalities in autism has broad implications for a wide range of work on the disorder including the design, validation, and interpretation of animal model, lymphocyte gene expression, brain gene expression, and genotype/CNV-anatomic phenotype studies.

Research Highlights

► During infancy and early childhood the autistic brain is marked by an abnormal overgrowth whereas during adolescence and adulthood there may be abnormal decline and possible degeneration. ► The genetic, molecular and cellular pathologies in autism that create the sudden and accelerated overgrowth during the first years of life must begin before that age period, namely during either prenatal or very early postnatal life. ► It is vital to elucidate the underlying neural impairments and decline in the older, including aging, autistic patient because there are presently no proven methods for successfully improving clinical symptoms at these ages.

Introduction

Recent research has led to the theory of age-specific anatomic abnormalities in autism (Courchesne et al., 2001, Courchesne et al., 2007, Courchesne and Pierce, 2005) (see Fig. 1). At early ages, there is abnormal overgrowth of the brain in autism, but during adolescence and young adulthood, there may be abnormal decline and possible degeneration (Fig. 1). Because early abnormal overgrowth occurs at the time of the first detectable behavioral and clinical signs of autism (Pierce et al., 2009, Pierce, in review) (Table 1), neural defects that cause overgrowth may be the neural bases of autism.

This theory was originally based on evidence from four studies in the early 2000s. First, in an MRI study, Courchesne et al. (2001) reported evidence of an unusual brain growth trajectory in autism. They discovered abnormal brain and cerebrum enlargement in autistic 2- to 4-year olds, but also observed slightly smaller overall brain volumes in autistic 12 to 16 year olds (Fig. 2). Subsequent studies also reported brain or cerebral overgrowth in autistic 2- to 4-year olds (Carper et al., 2002, Sparks et al., 2002, Hazlett et al., 2005, Bloss and Courchesne, 2007, Schumann et al., 2010), while autistic adolescents and adults have been reported to display cortical atrophy (Hadjikhani et al., 2006) and reduction in amaygdala (Aylward et al., 1999, Pierce et al., 2004) and frontal cortex volumes (Kosaka et al., 2010) (reviews: Amaral et al., 2008, Courchesne et al., in press). Moreover, meta-analyses of MRI brain volume in the autism literature (Redcay and Courchesne, 2005, Stanfield et al., 2008) and postmortem autistic brain weight (Redcay and Courchesne, 2005) also confirm early brain overgrowth in autism by 2 to 6 years of age.

Second, based on analyses of head circumference (HC), it was discovered that this abnormal brain enlargement is not present at birth in most cases but instead begins during the first 2 years of postnatal life (Courchesne et al., 2003). Multiple HC studies since then have also found early pathological HC overgrowth in the first postnatal years (Hazlett et al., 2005, Dementieva et al., 2005, Dissanayke et al., 2006, Dawson et al., 2007, Mraz et al., 2007, Webb et al., 2007, Elder et al., 2008, Fukumoto et al., 2008).

Third, Carper et al (2002) determined that this overgrowth had an important gradient in the cerebrum: greatest in frontal and temporal cortices and least in occipital (Fig. 3). This finding has also been reported in subsequent studies (Schumann et al., 2010; reviews: Courchesne et al., 2007, Courchesne et al., in press) (Fig. 3).

Finally, Dawson and colleagues (Sparks et al., 2002) discovered overgrowth of the amygdala, a structure vital to emotional processing and memory, in autistic 4-year olds. Subsequent studies have verified and extended these findings showing associations between degree of overgrowth and severity of clinical symptoms (Munson et al., 2006, Mosconi et al., 2009, Schumann et al., 2009). The underlying neural defects that cause overgrowth in frontal and temporal cortices and the amygdala have yet to be identified. Whatever these underlying early defects may be, they will likely explain why autistic behavior develops and provide clues as to the genetic or non-genetic factors that trigger those overgrowth defects.

Thus, many MRI studies have found abnormal early overgrowth in several regions that mediate the development of higher order social, emotion, language, and communication abilities, namely, frontal and temporal cortices and the amygdala (reviews: Courchesne et al., 2007, Amaral et al., 2008, Courchesne et al., in press). Nonetheless, how anatomic pathology alters with age after these early years is little studied. To gain insight into this question, two studies (Redcay and Courchesne, 2005, Stanfield et al., 2008) conducted formal statistical meta-analyses of a large number of separate reports, each of which represented a different relatively narrow age window. Both meta-analyses showed statistical evidence suggestive of substantial age-related changes in the degree of deviation from normal in brain size in autism.

However, as recently pointed out (Courchesne et al., in press), no single study has ever directly examined age-related changes across early life to adulthood in autism because of the difficulty in collecting MRI scans across such a wide age range in autistic and healthy typical subjects. Without direct evidence, age-related differences in pathology at younger versus older ages remain no more than a statistical inference from these meta-analyses.

Here, in the largest autism MRI sample ever analyzed, we report in 2- to 50-year olds the first direct longitudinal and cross-sectional MRI evidence in support of the theory of age-specific anatomical abnormality in autism. We found strikingly different pathological trajectories in brain size during early as compared to later life in autism, with overgrowth evident in early life but an accelerated rate of decline marking adult life.

Section snippets

Results

Growth curves of overall brain size across the life span from 2 to 50 years of age in ASD are shown in Fig. 4. The growth curves reveal an early period of brain overgrowth in ASD boys and girls followed by slowed growth during later childhood when the normal brain catches up with that of the autistic brain volumes. Thereafter, brain volumes decrease in size in ASD at a faster rate than normal so that, in ASD males, by later adulthood, the brain is slightly smaller than average.

This very large

Discussion

The genetic, molecular, and cellular pathologies in autism that create the sudden and accelerated overgrowth during the first years of life must begin before that early age period, namely during either prenatal or very early postnatal life. We theorize that the abnormally accelerated rate of early growth and then premature arrest of growth in the autistic brain signal innate abnormalities of initial cortical neural and laminar organization and connectivity that are not the result of experience

Experimental procedures

To further test the theory of age-specific anatomic abnormalities in autism, we analyzed 586 longitudinal and cross-sectional MRI scans from N = 259 ASD subjects ages 2 to 50 years and N = 327 typical subjects ages 1 to 50 years. This is many times larger than any previous MRI autism dataset and incorporates longitudinal MRI evidence from both young as well as much older autism and typically developing subjects. This large dataset encompasses MRI scans from our studies conducted across the past 18 

Acknowledgments

The writing of this article was made possible by grants from the National Institute of Mental Health (E. Courchesne, 1-P50-MH081755, 2-R01-MH036840), the National Institute of Neurological Disorders and Stroke (Grant 2-ROI-NS19855), National Institute of Mental Health (K. Pierce, R01-MH080134), Autism Speaks, and the Simons Foundation. We send many thanks to all of the children and parents who participate in autism research.

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