What is Chronic Traumatic Encephalopathy?
Chronic traumatic encephalopathy (CTE) is a progressive neurodegenerative disease affecting people who have suffered repeated concussions and traumatic brain injuries (TBI). CTE was first described in 1928 by Dr. Harrison Martland as “Punch-drunk syndrome” observed amongst former boxers. Later in 2005, the work of Dr. Omalu and colleagues garnered a great deal of attention from the lay press as CTE was observed in former National Football League (NFL) players.
Dr. Omalu was the first to identify, describe and label the disease as CTE. The symptoms of CTE typically begin to emerge 8−10 years after the injury and include behavioral and mood changes, memory loss, cognitive impairment, and dementia1.
CTE is a rare and complex disorder, and its mechanism is not well understood. Therefore, there are no biomarkers available for diagnosis nor any established mode of treatment. It is still not very clear how repeated head traumas and severity of trauma contribute to the changes in the brain that result in CTE.
Interestingly, not all individuals who have had head injuries go on to develop CTE. There is some debate in the literature that APOE ε4 allele may contribute towards a genetic susceptibility to CTE, although more studies are required to definitively establish a correlation2.
Pathophysiology of CTE
One of the pathophysiological mechanisms observed in CTE is an accumulation of hyper-phosphorylated tau protein (p-tau), similar to what occurs in Alzheimer’s disease. Tau is a microtubule-associated protein, abundant in the neurons of the central nervous systems (CNS) and plays a role in maintaining the stability of axonal microtubules. Head trauma results in a breakdown of the tau-microtubule complex, possibly leading to disruption of axonal transport, shearing of nerve fibers, release of tau proteins, and accumulation of tau tangles.
Neuroinflammation, which is critical to both neuroprotection and neurotoxicity, is another component that drives the progression of CTE. Microglia and astrocytes are key mediators of neuroinflammation in the CNS as they release inflammatory cytokines after an injury.
Microglia are activated by the accumulation of hyperphosphorylated tau proteins and are involved in several homeostatic processes including synaptic pruning, immune surveillance, and debris clearance. However, persistent microglia-mediated inflammation is the cause of neuronal dysfunction and continuous tissue damage long after the initial injury.
Little is known about the precise molecular mechanism that drives the chronic neuroinflammation in CTE. Several studies have attempted to understand microglia biology and its role in TBI pathogenesis of CTE. Studies from Witcher et. al showed that microglial depletion reversed TBI-related expression of genes associated with inflammation, establishing microglia as key players in the progression of CTE3.
The rapidly evolving field of spatial biology has provided an opportunity for researchers to investigate differential gene expression in activated microglia in different locations within brain tissue. Furthermore, the nCounter® Analysis System has helped quantify gene expression in a mouse model for TBI. This study identified time-dependent and injury-associated changes in microglial gene expression4.
Differential gene expression resulted in the loss of microglia to sense tissue damage, perform housekeeping, and maintain homeostasis, thus transitioning the microglia from a neuroprotective state to a neurotoxic state causing inflammation over time. Nevertheless, it is still unclear what factors contribute toward differential gene expression in these microglia in TBI.
Microglial cells are like the macrophages of the brain and the first responders to infection and brain injury. Like macrophages, microglia change their morphology when activated.
Microglia activation in TBI results in different phenotypes, corresponding to neurotoxic or neuroprotective priming states. Depending on the stage of the disease and its chronicity, microglia are stimulated differentially, and this leads to certain activation states, which correspond to altered microglia morphology.
The GeoMx® Digital Spatial Profiler (DSP) could help understand the significance of functional changes in microglia morphology. For example, GeoMx DSP can resolve gene and protein expression patterns while at the same time quantify location in a specific microglial population across many samples. Knowledge of microglia activation states is crucial to understanding how microglia organize and interact with their surrounding environment to drive chronic inflammation.
Diagnosis and Biomarker
Currently, CTE can solely be diagnosed postmortem based on the spatial pattern of tau-accumulation. Discovering biomarkers to diagnose CTE in living subjects has been a major challenge. A recent study identified 25 different dysregulated exosomal microRNAs in the plasma of patients with chronic TBI5. Due to their small size, miRNAs freely move across the blood-brain barrier (BBB) into the peripheral circulation, making them ideal candidates for biomarkers.
The nCounter® miRNA Expression Panel as used to quantify miRNA expression changes associated with neuroinflammation. Some of the exosomal microRNAs identified were associated with genes such as vascular endothelial growth factor A (VEGFA), Nuclear factor IA (NFIA), and synuclein gamma (SNCG) that are involved in neuroprotection, memory, and synaptic plasticity; thus, offering insights into the molecular mechanisms underlying functional brain injuries. However, the application of an unbiased assay such as the GeoMxWhole Transcriptome Atlas would be more valuable as it can be used to spatially profile the entire human or mouse transcriptome on CTE brain samples, increasing the likelihood of identifying biomarkers.
Currently, there are no targeted pharmacologic therapies to prevent TBI-related symptoms. As we advance our knowledge into various molecular and cellular drivers of neuroinflammation with gene profiling technologies such as GeoMx DSP, a map of disease-related changes in gene expression for CTE can be created. Such a map would be a valuable tool in not only offering mechanistic insights into CTE but would open up opportunities for therapeutic intervention.
Currently, there are three clinical trials that assessed the effects of the anti-inflammatory drugs cyclosporine and minocycline. However, these studies used small sample sizes and there was an increased incidence of adverse events and levels of injury markers. A larger study and a thorough investigation of the neuroprotection function of these drugs are required.
Are you in the field of TBI and CTE? How would you use spatial biology in your work?
For Research Use Only. Not for diagnostics procedure.
1. McKee AC. The Neuropathology of Chronic Traumatic Encephalopathy: The Status of the Literature. Semin Neurol. 2020 Aug;40(4):359-369.
2. Deng H, Ordaz A, Upadhyayula PS, et al. Apolipoprotein E Epsilon 4 Genotype, Mild Traumatic Brain Injury, and the Development of Chronic Traumatic Encephalopathy. Med Sci (Basel). 2018 Sep 14;6(3):78.
3. Witcher KG, Bray CE, Chunchai T, et al. Traumatic Brain Injury Causes Chronic Cortical Inflammation and Neuronal Dysfunction Mediated by Microglia. J Neurosci. 2021 Feb 17;41(7):1597-1616.
4. Izzy S, Liu Q, Fang Z, et al. Time-Dependent Changes in Microglia Transcriptional Networks Following Traumatic Brain Injury. Front Cell Neurosci. 2019;13:307.
5. Vorn R, Suarez M, White JC, et al . Exosomal microRNA Differential Expression in Plasma of Young Adults with Chronic Mild Traumatic Brain Injury and Healthy Control. Biomedicines. 2021 Dec 24;10(1):36.