NEUROLOGY & NEUROSURGERY

Post Subarachnoid Hemorrhage Syndrome: Transcriptome Changes in Mouse Model Offers Potential Roadmap

Nov. 11, 2021 - Eden McCleskey

The vast majority of patients who suffer a subarachnoid hemorrhage (SAH), bleeding in the space that surrounds the brain, report cognitive deficits such as impaired memory, decreased executive function and emotional disturbance.

Such long-term cognitive effects, known as post-SAH syndrome, are thought to result from damage to the temporomesial-hippocampal areas, but the underlying mechanisms remain unclear. Even patients who show no brain tissue injury and don't experience hydrocephalus, paralysis, weakness or physical effects of a stroke are affected by the syndrome, a puzzle researchers have been investigating for several decades.

Now, Houston Methodist researchers are hoping their gene-based mouse study reveals the cascade of events that cause subarachnoid hemorrhage's long-term cognitive deficits.

Trying a new approach

To gain a deeper understanding about what's going on in the patient's brain than even the most sophisticated imaging or cognitive testing can provide, Dr. Gavin Britz, chair of the Houston Methodist Department of Neurosurgery, Dr. Eugene Golanov and Angelique Regnier-Golanov performed a systematic RNA sequencing screen of the hippocampus in a mouse model of SAH. Their findings, published in Frontiers in Neurology, suggest that inflammation, the complement immune response and myelin may play a critical role in cognitive changes after SAH.

"By analyzing the up-regulation and down-regulation of specific genes in our mouse model of SAH, we gain a better understanding of what systems are involved and can begin to trace these genetic breadcrumbs to identify the likely sequence of events causing these cognitive symptoms," Dr. Britz says.

A complicated sequence

The researchers believe these genetic changes point to the following explanation:

  • The aneurysmal rupture causes blood to accumulate on the outside of the brain, where it's not supposed to be.
  • This stimulates the perforant pathway, which leads from the entorhinal cortex into the hippocampus, and triggers the complement immune system proteins.
  • The resulting cascade of inflammation damages this pathway, causing pruning of the dendritic spines and leading to myelin loss.
  • Myelin loss is associated with the type of progressive cognitive symptoms experienced by patients months, years, even decades after SAH.

"These findings confirm that it's not the aneurysm causing a direct hit in the brain, leading to cell death and loss of function, it's a multifactorial process that occurs over time," Dr. Britz summarizes.

Moving in the right direction

Differential gene expression analysis detected 642 up-regulated and 398 down-regulated genes in SAH compared to the control group.

This was the first study to create a systematic gene and pathway database of the hippocampal response after SAH.

"Identifying the novel pathways may allow for the development of new therapeutic approaches to prevent cognitive deficits after subarachnoid hemorrhage," Dr. Britz says. "This was an important first step in that direction."