Postmortem studies of autism.

03Original abstract

The neuropathological basis of autism is a relatively neglected area of study that merits more attention if we are to gain a proper understanding of the neurobiology of ASDs. The first neuropathological studies were not published until the 1980s and this slow start probably reflected scepticism that much would be learnt from the study of the brain postmortem, especially as studies of Mental Retardation had not led to significant mechanistic advances. The perceived challenge of discussing brain donation with relatives either before or after death probably also held back the field until the need for donation became more openly discussed. Moreover, the long time course of postmortem tissue collection and study, and uncertainty about possible outcomes have not been a good fit with grant calls demanding significant clearly described deliverables. Nevertheless, despite the rather hesitant start, the field has seen a significant quickening in pace over the last decade. This acceleration reflects the much greater current emphasis on understanding the neurobiology of autism and the role of charities in organizing and promoting tissue collection and study. In fact neuropathological studies occupy a pivotal position between the approaches of molecular biology and systems neuroscience. Significant money and effort have been invested in identifying susceptibility genes for ASDs because success will inform us about the biochemical pathways involved. Nevertheless, many genes have multiple roles in brain development and function, and identifying the role that is most important in the development of ASD will be aided significantly by evidence of abnormalities in brain development and structure. Additionally, a key aim of developing mouse models of susceptibility genes is to understand the neuropathological consequences of risk alleles, but this effort is hampered if there is no human data for comparison. Neuropathological studies can also provide clues about the timing of abnormal developmental processes, which may steer our search for potential interacting environmental factors. The last decade has also seen a huge increase in neuroimaging studies of autism, with a strong focus on brain structure, localization of function and, most recently connectivity. There is real excitement in this field as the potential to identify the brain correlates of cognitive difficulties and behavioral differences is so clear. Nevertheless, we also need to understand the processes that led to identified differences in structure and function, and that goal requires knowledge of brain organization at the cellular level. Although the potential of neuropathological studies is clear, there are major practical and scientific challenges in moving the science forward. One key issue is the very modest numbers of brains that are currently available for study. Expanding brain collection systematically within Europe would help, although language differences increase the organizational and administrative burden of that route. But even where tissue collection is already well established, there is much more that could be done to increase the rate of donation, especially among those families who are no longer active members of parental organizations. Additionally, most published studies have been of tissue from severely affected individuals, in which autism has been accompanied by Mental Retardation and often epilepsy. Of course we do need to identify the brain basis of Mental Retardation and epilepsy in autism because they are major determinants of outcome and morbidity. However, we also need to study tissue from individuals across the autistic spectrum if we are to really understand the relationship between neuropathology and symptomatology, and that will require reaching out directly to affected individuals and not just to relatives. Just as important is the need to obtain suitable control tissue. This is a particular problem with respect to age matching, and although one can obtain tissue from other countries, this option involves assumptions about ethnic differences and a minimal role for nutritional and environmental differences that may be unwarranted. With respect to the focus of new studies, grant-giving bodies should recognize that the field remains wide open. Presently, we do not know whether we should concentrate on synapses, dendritic structure, the cell body, axonal projections and myelin, cell position and orientation, particular subclasses of cells, or all of these areas. Indeed the multiplicity of abnormalities already reported means we will likely need molecular genetic findings to help identify whether any of these abnormalities are truly primary. Further neuropathological study of Tuberous Sclerosis and Fragile X, with and without ASD, may also guide future work. If charities, grant-giving bodies, families, and researchers can rise to these diverse challenges, there is the very real hope that finally we may be able to link together etiology, molecular biology, neuropathology, and systems neuroscience, which will ultimately benefit patients.

Autism research : official journal of the International Society for Autism Research, 2008 · doi:10.1002/aur.51