Nature Reviews Neurology | 2021
Deep learning distinguishes tauopathies
Abstract
0123456789();: Cortical thinning in the brains of people with epilepsy correlates with the distribution of activated microglia, new research published in Neuropathology and Applied Neurobiology indicates. The study, conducted by the ENIGMA-Epilepsy Working Group, also showed that transient microglial depletion prevented seizure-associated cortical thinning in mice, suggesting a potential strategy to protect the cortex from seizure-induced damage. “In the first ENIGMA study, which was published in 2018, Whelan et al. showed that epilepsy was associated with widespread and distinct patterns of cortical thinning,” explains co-corresponding author Sanjay Sisodiya. “In the current study, we have tried to identify the mechanisms of the thinning to determine if it might be prevented.” By combining data on cortical thinning from the Whelan et al. study with gene expression data from the Allen Human Brain Atlas, the researchers found evidence that microglial and endothelial cell densities were increased in cortical regions that were vulnerable to thinning. Markers of activated microglia were particularly highly expressed in these regions, and post-mortem investigations confirmed the presence of large numbers of activated microglia in the brains of people with chronic epilepsy. To further explore the relationship between microglial activation and cortical thinning, the authors examined the effects of transient microglial depletion, using the tyrosine kinase inhibitor PLX3397, in a mouse model of acquired epilepsy. This intervention was found to prevent cortical thinning in some regions but had no effect on the development of seizures, implying that these two processes are dissociable. “This is a really important finding and might help explain how outcomes in epilepsy can be poor even if seizures are controlled,” comments Sisodiya. “Experiments in mice also showed that cortical thinning was associated with both neuronal cell loss and cognitive deficits on a behavioural test involving the entorhinal cortex — one area that undergoes thinning in epileptic mice and in humans with epilepsy,” adds co-corresponding author Annamaria Vezzani. “The animal data showed that microglia are involved in these effects in the early phases of epilepsy development.” The researchers acknowledge that the cell types and mechanisms involved in epilepsy-associated cortical thinning require further investigation. The possible benefits of microglial manipulation in humans with epilepsy also remain to be explored: although PLX3397 has already been approved by the FDA for the treatment of tenosynovial giant cell tumour, the essential role of microglia in normal physiological responses to brain insults might limit the applications of this drug in the context of epilepsy.