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Autism BRAIN Stereology Project – 12 YEARS and Counting

Thursday, 2 May 2013: 14:00-18:00
Banquet Hall (Kursaal Centre)
J. A. Pickett1, P. R. Hof2 and J. Wegiel3, (1)Autism Tissue Program, Autism Speaks, San Diego, CA, (2)Neuroscience, Mount Sinai School of Medicine, New York, NY, (3)New York State Institute for Basic Research, Staten Island, NY
Background: A fundamental part of brain banking is the neuropathologic examination of portions of 20 or more major brain regions, examined microscopically.  In 2001, two investigators independently proposed projects that altered the processing and evaluation of brains by adding a stereology focus to examine whole brain hemispheres, not just selected portions.  In the same year, a Neuropathology of Autism focus group recommended that post mortem brains be imaged (MRI) when possible.  The interests culminated in a joint project funded by Autism Speaks titled Clinicopathological Correlations in Autism.  It included MRI and comprehensive stereology of age- and gender-matched hemispheres.   

Objectives: To find cellular correlates of gross alterations seen in the autism brain by in vivo imaging studies within a protocol of systematic stereologic study of whole hemispheres. The data will contribute to understanding the clinical course of autism as well as defining circuits that are amenable to pharmacological treatment.  An important component of the Project is the availability of unstained sections and stained slides to other researchers and analysis of results reported by the participants.  The early projection of the final subject cohort was 10 autism and 10 control hemispheres ranging from age 2 to 75.     

Methods: The Project combines imaging techniques, computer-based image analysis, computer-based stereology (unbiased methods to estimate morphometric parameters such as number, density or volumes of cells), immunochemical staining of cell components, and neuropathology.  Special attention is paid to donor phenotype with documentation of testing and medical histories of the donor and family.  Collaborating laboratories image the formalin-fixed hemispheres, embedding in celloidin and sectioning ~seven hundred 200 µm-thick sections.  One-third is stained with cresyl violet, 1/3 with gallocyanin, and the remaining 1/3 sections are preserved in ethanol; all are available upon request/approval by the ATP’s Tissue Advisory Board.  The two principal investigators explored the number, size, and spatial arrangement of neurons in the fusiform gyrus and the frontoinsular, anterior cingulate and inferior temporal cortices as well as the memory system (entorhinal cortex, hippocampus, amygdala), the sensorimotor system (basal ganglia, nucleus accumbens, substantia nigra), cerebellum and brainstem.  The research has been supported by a number of brain banks and funded by Autism Speaks, the author’s institutions, NIH, and DOD grants since 2002. 

Results: Forty-two hemispheres have been processed; 30 males and 12 females; 23 autism and 19 controls.  With the best age-gender-laterality matching, there are 14 hemispheric pairs for the core comparative analysis.  Imaging, cell counting, and neuropathologic examinations have been ongoing since 2001 with the target regions to be completed by the end of 2012. These data will be presented at IMFAR and made available of the ATP portal.  

Conclusions: The Brain Atlas Project was conceived to provide information about the brains of males and females with autism relative to known pathological processes and also relative to unaffected control brains of the same maturation (age).  The data serve as a baseline for further studies and will be of immediate importance to an additional 10-12 laboratories also studying this cohort.

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