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IL-6 tied to brain structure changes in areas related to neurological conditions

JAMA Psychiatry
Reuters Health - 05/04/2022 - Genetically determined IL-6 (IL-6) levels were associated with brain structure and gray matter volume in brain regions associated with such conditions as schizophrenia, autism spectrum disorder, and epilepsy in multiple linked genetic analyses. 

"Existing research, including that previously conducted by the PIMS (Psychosis Immune Mechanism Stratified Medicine Study) collaboration (https://bit.ly/3LGQoWb), suggests that inflammation may have an important role to play in mental health disorders," Dr. Rachel Upthegrove of the University of Birmingham, UK, told Reuters Health by email. 

"We suspected IL-6 may have a pivotal role," she said. "However, results for the association between the IL-6 receptor and brain structure were very specific - no other tested inflammatory marker was significant after correction for multiple testing." 

In addition, she said, "IL-6 appears to affect brain areas that are important for mental health - i.e., temporal and frontal areas." 

As reported in JAMA Psychiatry, to investigate the relationship between inflammation and changes in brain structures in vivo, the researchers used multistage linked analyses, including mendelian randomization (MR), gene expression correlation, and connectivity analyses. 

Genetic variants regulating levels and activity of circulating interleukin 1 (IL-1), IL-2, IL-6, C-reactive protein (CRP), and brain-derived neurotrophic factor (BDNF) were used as exposures in MR analyses. 

A total of 20,688 participants (mean age, 55.5; about 52%, women) from the UK Biobank were included in the analyses. The Biobank includes clinical, genomic, and neuroimaging data, as well as six postmortem brains from neurotypical individuals in the Allen Human Brain Atlas (AHBA). 

In the Biobank sample, genetically predicted levels of IL-6 were associated with gray matter volume in the middle temporal cortex, inferior temporal, fusiform, and frontal cortex together with cortical thickness in the superior frontal region. 

No significant associations were found for IL-1, IL-2, CRP, or BDNF after correction for multiple comparisons. 

In the AHBA sample, patients had a mean age of 42.5 and five of the six (83%) were men. Brain-wide coexpression analysis showed a highly interconnected network of genes preferentially expressed in the middle temporal gyrus (MTG), which also formed a highly connected protein-protein interaction network with IL-6. 

MTG differentially expressed genes that were functionally enriched for biological processes in schizophrenia, autism spectrum disorder, and epilepsy. 

Dr. Upthegrove said, "We need to take this information and build on how IL-6 may prove a new target for better treatments. Our next step is to begin an experimental medicine study, due to open soon, where we will test the effect of tocilizumab, a medication used in rheumatoid arthritis, and the effect this may have on IL-6-related brain changes and symptoms." 

"Many further clinical studies...are needed before a firm connection can be proven or disproven," she added. 

Dr. Robert Bermel, Director of Cleveland Clinic's Mellen Center for Multiple Sclerosis in Ohio, commented on the study in an email to Reuters Health, "This work...generates provocative hypotheses that may expose undiscovered mechanisms of disease in neuropsychiatric disorders. These hypotheses can and should be tested in more formal studies in people afflicted by schizophrenia, autism, and other implicated disorders." 

"The hope is that new hypotheses like this will open a door to new treatment modalities," he concluded. 

SOURCE: https://bit.ly/3J67dbq JAMA Psychiatry, online March 30, 2022. 

By Marilynn Larkin 


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