Abnormally low levels of a key protein in brains of young men with autism

Summary: Males on the autism spectrum have significantly lower levels of a protein in their brains’ that plays a role in inflammation and metabolism.

Source: Mass General

Using cutting-edge imaging technology, researchers at Massachusetts General Hospital (MGH) have shown that the brains of young men with autism spectrum disorder (ASD) have low levels of a protein that appears to play a role in inflammation and metabolism. This surprising discovery, which published online today in the journal Molecular Psychiatry provides an important new insight into the possible origins of ASD, which affects one in 59 children.

ASD is a developmental disorder that emerges in early childhood and is characterized by difficulty communicating and interacting with others. While the cause is unknown, growing evidence has linked ASD to inflammation of brain tissue, or neuroinflammation. One sign of neuroinflammation is elevated levels of a substance called translocator protein (TSPO), which can be measured and located in the brain using positron-emission tomography (PET) and anatomical magnetic resonance imaging (MRI). The MGH study, led by Nicole Zurcher, PhD, an investigator in MGH’s Athinoula A. Martinos Center for Biomedical Imaging, was the first to use a new generation of PET “tracers,” which more accurately detect TSPO, to examine the brains of people with ASD.

In the study, Zurcher and her colleagues scanned the brains of 15 young adult males (average age, 24) with ASD. The group included both high- and low-functioning subjects with varying degrees of intellectual abilities. For comparison, Zurcher’s team scanned the brains of 18 healthy control subjects who were similar in age. The investigators hypothesized that the scans would show increased levels, or expression, of TSPO in subjects who have ASD.

“To our surprise, that’s not what we saw,” says Zurcher. Instead, the scans showed that the brains of males with ASD had lower levels of TSPO than those of the healthy subjects. In fact, the men with the most severe symptoms of ASD tended to have the lowest expression of TSPO. When the tests were repeated several months later, the pattern persisted. The brain regions found to have low expression of TSPO have previously been linked to ASD in earlier studies, and are believed to govern social and cognitive capacities such as processing of emotions, interpreting facial expressions, empathy, and relating to others. “We know these brain regions are involved in autism,” says Zurcher.

This shows a drawing of a brain and a hand

To understand this unexpected finding, Zurcher notes that TSPO does more than serve as a marker of inflammation. Image is in the public domain.

To understand this unexpected finding, Zurcher notes that TSPO does more than serve as a marker of inflammation. “It has multiple complex roles,” she says, and some actually promote brain health. For example, adequate TSPO is necessary for normal functioning of mitochondria, which are the “power houses” in cells that produce energy. Earlier research has linked malfunctioning mitochondria in brain cells to ASD.

Zurcher and her colleagues next plan to study brains from deceased donors with the goal of determining which brain cells in people with ASD might experience mitochondrial dysfunction, which she says may well be occurring alongside neuroinflammation and other mechanisms to cause ASD. “Our study has generated new hypotheses that now need to be investigated,” says Zurcher. “There’s more work to be done.”

The lead author of the Molecular Psychiatry study is Nicole Zurcher, PhD, an assistant investigator in MGH’s Athinoula A. Martinos Center for Biomedical Imaging and an instructor in Radiology at Harvard Medical School (HMS). The senior author is Jacob Hooker, PhD, director of Radiochemistry at the Martinos Center and an associate professor in Radiology at HMS.

About this autism spectrum disorder research article

Source:
Mass General
Media Contacts:
Terri Janos – Mass General
Image Source:
The image is in the public domain.

Original Research: Open access
“[11C]PBR28 MR–PET imaging reveals lower regional brain expression of translocator protein (TSPO) in young adult males with autism spectrum disorder”. N. R. Zürcher, M. L. Loggia, J. E. Mullett, C. Tseng, A. Bhanot, L. Richey, B. G. Hightower, C. Wu, A. J. Parmar, R. I. Butterfield, J. M. Dubois, D. B. Chonde, D. Izquierdo-Garcia, H. Y. Wey, C. Catana, N. Hadjikhani, C. J. McDougle & J. M. Hooker.
Molecular Psychiatry doi:10.3389/fmed.2020.00006.

Abstract

[11C]PBR28 MR–PET imaging reveals lower regional brain expression of translocator protein (TSPO) in young adult males with autism spectrum disorder

Mechanisms of neuroimmune and mitochondrial dysfunction have been repeatedly implicated in autism spectrum disorder (ASD). To examine these mechanisms in ASD individuals, we measured the in vivo expression of the 18 kDa translocator protein (TSPO), an activated glial marker expressed on mitochondrial membranes. Participants underwent scanning on a simultaneous magnetic resonance–positron emission tomography (MR–PET) scanner with the second-generation TSPO radiotracer [11C]PBR28. By comparing TSPO in 15 young adult males with ASD with 18 age- and sex-matched controls, we showed that individuals with ASD exhibited lower regional TSPO expression in several brain regions, including the bilateral insular cortex, bilateral precuneus/posterior cingulate cortex, and bilateral temporal, angular, and supramarginal gyri, which have previously been implicated in autism in functional MR imaging studies. No brain region exhibited higher regional TSPO expression in the ASD group compared with the control group. A subset of participants underwent a second MR–PET scan after a median interscan interval of 3.6 months, and we determined that TSPO expression over this period of time was stable and replicable. Furthermore, voxelwise analysis confirmed lower regional TSPO expression in ASD at this later time point. Lower TSPO expression in ASD could reflect abnormalities in neuroimmune processes or mitochondrial dysfunction.

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