Brain Inflammation Linked to Autism
Abstract & Commentary
By Barry E. Kosofsky Attending Pediatrician, New York Presbyterian Hospital, Professor, Cornell Medical College, Research Associate, Massachusetts General Hospital Dr. Kosofsky reports no consultant, stockholder, speaker’s bureau, research, or other financial relationships with companies having ties to this field of study.
Synopsis: This article reports the findings from a neuropathologic study of brain tissue and CSF from autistic patients suggesting an inflammatory-mediated component to this syndrome.
Source: Vargas DL, et al. Neuroglical Activation and Neuroinflammation in Brain of Patients with Autism. Ann Neurol. 2005;57:67-81.
Autism is a disorder which is defined by the DSM-IV as a qualitative impairment in social interaction, a qualitative impairment in communication, and restrictive repetitive and stereotypic patterns of behavior, interests, and activities. Recent studies have suggested an increase in the prevalence of this disorder, thereby, gathering greater public and media attention. Multiple hypotheses including pathological, immunological, environmental, and even iatrogenic contributions to this disorder have been generated.
This neuropathologic report is a case control study displaying an active inflammatory response in CSF samples and post-mortem brain tissue of autistic patients. Brain samples from autistic and control cases were collected from a multi-center Autism Tissue Consortium (including Brain Banks at Harvard, the University of Miami, and the University of Maryland). Autistic cases were defined by DSM-IV criteria and, subsequently, confirmed by the Autism Diagnostic Interview-Revised. Autopsys of brain tissue were conducted on 11 autistic patients and 6 controls. Regions selected for study included the middle frontal gyrus, anterior cingulate gyrus, and cerebellar hemisphere. CSF samples from autistic and control patients were obtained from the Johns Hopkins Neurology CSF repository. The pathology studies used included immunocytochemical staining and confocal microscopy-based quantitative analyses of immunoreactivity for GFAP and HLA-DR, protein tissue arrays, and ELISA studies.
The study shows an increase in innate immune reactivity rather than adaptive immunity in triggering neuroglial activation, a process which was significantly more evident in the brains and CSF of autistics vs controls. Neuropathological studies revealed increased microglial and astroglial activation in all brain areas studied, which was most evident in the cerebellum. Specifically, in the autistic brains, patchy neuronal loss was observed most prominently in the Purkinje cell layers and the granular cell layers of the cerebellum. These were not found in the control samples. In comparison to controls, GFAP immunostaining of the autistic brains revealed increased astroglial activation and reactivity in all regions studied. Immunocytochemical staining for MHC class II markers revealed increased microglial activation more prominently in the cerebellum, as well as the cortex of autistics vs controls. Age, history of developmental regression, or mental retardation in the autistics did not appear to make a significant difference in the amount of microglial or astroglial activation. However, history of epilepsy accounted for elevated microglial activation, which was restricted to the cerebellar white matter of autistic patients.
Other major pathologic findings were the lack of adaptive immunity in the autistic patients. In particular, there was lack of specific T-cell responses and antibody-mediated reactions. However, there was a significant finding of membrane attack via complement, which formed complexes in the purkinje cell and and granular cell layer of the cerebellum. This suggests a possible mechanism of brain damage via microglial activation, triggering complement activation, leading to neuronal loss in the cerebellum.
Brain and CSF studies of autistic patients revealed differences in cytokine expression. In the autistic brains, MCP-1 and TARC (pro-inflammatory chemokines) and TGF-B1 (an anti-inflammatory cytokine) were increased. MCP-1 was found to be significantly increased in both brain and CSF samples. CSF studies from 6 living autistics and 6 controls (without documented CNS pathology) revealed a 12-fold increase in MCP-1 levels. Other proinflammatory and modulatory cytokines and growth factors were also significantly increased.
Commentary
Vargas and colleagues suggest that these findings may reflect disease chronicity, but their findings do not preclude the possibility that these immune mechanisms are invoked in earlier stages of autism. Whether inflammatory changes in the brains of autistics are the cause or the consequence of this disorder remains to be determined. Likewise, it will be important to establish whether such immune mechanisms contribute to disease progression in a subset of patients with this syndrome. If such a subset could be identified with genetic and/or CSF markers, that would have both diagnostic and therapeutic implications.
This article reports the findings from a neuropathologic study of brain tissue and CSF from autistic patients suggesting an inflammatory-mediated component to this syndrome.
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