Inflammasome links traumatic brain injury, chronic traumatic encephalopathy, and Alzheimer's disease

Traumatic brain injury, chronic traumatic encephalopathy, and Alzheimer's disease are three distinct neurological disorders that share common pathophysiological mechanisms involving neuroinflammation. One sequela of neuroinflammation includes the pathologic hyperphosphorylation of tau protein, an endogenous microtubule-associated protein that protects the integrity of neuronal cytoskeletons. Tau hyperphosphorylation results in protein misfolding and subsequent accumulation of tau tangles forming neurotoxic aggregates. These misfolded proteins are characteristic of traumatic brain injury, chronic traumatic encephalopathy, and Alzheimer's disease and can lead to downstream neuroinflammatory processes, including assembly and activation of the inflammasome complex. Inflammasomes refer to a family of multimeric protein units that, upon activation, release a cascade of signaling molecules resulting in caspase-induced cell death and inflammation mediated by the release of interleukin-1β cytokine. One specific inflammasome, the NOD-like receptor protein 3, has been proposed to be a key regulator of tau phosphorylation where it has been shown that prolonged NOD-like receptor protein 3 activation acts as a causal factor in pathological tau accumulation and spreading. This review begins by describing the epidemiology and pathophysiology of traumatic brain injury, chronic traumatic encephalopathy, and Alzheimer's disease. Next, we highlight neuroinflammation as an overriding theme and discuss the role of the NOD-like receptor protein 3 inflammasome in the formation of tau deposits and how such tauopathic entities spread throughout the brain. We then propose a novel framework linking traumatic brain injury, chronic traumatic encephalopathy, and Alzheimer's disease as inflammasomedependent pathologies that exist along a temporal continuum. Finally, we discuss potential therapeutic targets that may intercept this pathway and ultimately minimize long-term neurological decline.

Diagnostic Prospectives with Tau Protein and Imaging Techniques to Detect Development of Chronic Traumatic Encephalopathy

Brain damage sustained from repeated blows in boxing, wrestling, and other combat sports has serious physical and mental health consequences. The degenerative brain disease, chronic traumatic encephalopathy (CTE), presents clinically with memory loss, aggression, difficulty in rational thinking and other cognitive problems. This spectrum, which mimics Alzheimer’s disease, is diagnosed post-mortem through a brain biopsy in many professional athletes. However, little is known about the process of development and how to identify vulnerable individuals who may be on course for developing CTE. Boxing is a sport that has a severe toll on athletes’ health, primarily on their brain health and function. This review addresses the concerns of brain injury, describes the pathologies that manifest in multiple scales, e.g., molecular and cognitive, and also proposes possible diagnostic and prognostic markers to characterize the early onset of CTE along with the aim to identify a starting point for future precautions and interventions.

Positron emission tomography imaging for the assessment of mild traumatic brain injury and chronic traumatic encephalopathy:recent advances in radiotracers

A chronic phase following repetitive mild traumatic brain injury can present as chronic traumatic encephalopathy in some cases,which requires a neuropathological examination to make a definitive diagnosis.Positron emission tomography(PET)is a molecular imaging modality that has high sensitivity for detecting even very small molecular changes,and can be used to quantitatively measure a range of molecular biological processes in the brain using different radioactive tracers.Functional changes have also been reported in patients with different forms of traumatic brain injury,especially mild traumatic brain injury and subsequent chronic traumatic encephalopathy.Thus,PET provides a novel approach for the further evaluation of mild traumatic brain injury at molecular levels.In this review,we discuss the recent advances in PET imaging with different radiotracers,including radioligands for PET imaging of glucose metabolism,tau,amyloid-beta,γ-aminobutyric acid type A receptors,and neuroinflammation,in the identification of altered neurological function.These novel radiolabeled ligands are likely to have widespread clinical application,and may be helpful for the treatment of mild traumatic brain injury.Moreover,PET functional imaging with different ligands can be used in the future to perform largescale and sequential studies exploring the time-dependent changes that occur in mild traumatic brain injury.

What triggers tauopathy in chronic traumatic encephalopathy?

Chronic traumatic encephalopathy（CTE）is a neuropathologically defined tauopathy：CTE is closely related with repetitive,traumatic brain injury.In a most recent study of 202 deceased players of American football from a brain donation program,CTE was neuropathologically diagnosed in 177 players across all levels of play （87%）, including 110 of 111 former National Football League players （99%） （Mez et al., 2017）.

Animal model of repetitive mild traumatic brain injury for human traumatic axonal injury and chronic traumatic encephalopathy

Chronic traumatic encephalopathy（CTE）is a chronic neurodegenerative disease featured with tauopathy.CTE is tightly related with repetitive mild traumatic brain injury（m TBI）,which is interchangeably known as concussion（Mc Kee et al.,2009,2013）.This disease is differentiated by neuropathological features from other neurological diseases that involve tau protein aggregation and tangle formation abnormalities like Alzheimer＇s disease （AD）, frontotemporal dementia, and Parkinson- ism linked to chromosome 17 （FTDP-17）.

Connecting cellular mechanisms and extracellular vesicle cargo in traumatic brain injury

Traumatic brain injury is followed by a cascade of dynamic and complex events occurring at the cellular level. These events include: diffuse axonal injury, neuronal cell death, blood-brain barrier break down, glial activation and neuroinflammation, edema, ischemia, vascular injury, energy failure, and peripheral immune cell infiltration. The timing of these events post injury has been linked to injury severity and functional outcome. Extracellular vesicles are membrane bound secretory vesicles that contain markers and cargo pertaining to their cell of origin and can cross the blood-brain barrier. These qualities make extracellular vesicles intriguing candidates for a liquid biopsy into the pathophysiologic changes occurring at the cellular level post traumatic brain injury. Herein, we review the most commonly reported cargo changes in extracellular vesicles from clinical traumatic brain injury samples. We then use knowledge from animal and in vitro models to help infer what these changes may indicate regrading cellular responses post traumatic brain injury. Future research should prioritize labeling extracellular vesicles with markers for distinct cell types across a range of timepoints post traumatic brain injury.

Depression following a traumatic brain injury:uncovering cytokine dysregulation as a pathogenic mechanism

A substantial number of individuals have long-lasting adverse effects from a traumatic brain injury（TBI）. Depression is one of these long-term complications that influences many aspects of life. Depression can limit the ability to return to work, and even worsen cognitive function and contribute to dementia. The mechanistic cause for the increased depression risk associated with a TBI remains to be defined. As TBI results in chronic neuroinflammation, and priming of glia to a secondary challenge, the inflammatory theory of depression provides a promising framework for investigating the cause of depression following a TBI. Increases in cytokines similar to those seen in depression in the general population are also increased following a TBI. Biomarker levels of cytokines peak within hours-to-days after the injury, yet pro-inflammatory cytokines may still be elevated above physiological levels months-to-years following TBI, which is the time frame in which post-TBI depression can persist. As tumor necrosis factor α and interleukin 1 can signal directly at the neuronal synapse, pathophysiological levels of these cytokines can detrimentally alter neuronal synaptic physiology. The purpose of this review is to outline the current evidence for the inflammatory hypothesis of depression specifically as it relates to depression following a TBI. Moreover, we will illustrate the potential synaptic mechanisms by which tumor necrosis factor α and interleukin 1 could contribute to depression. The association of inflammation with the development of depression is compelling; however, in the context of post-TBI depression, the role of inflammation is understudied. This review attempts to highlight the need to understand and treat the psychological complications of a TBI, potentially by neuroimmune modulation, as the neuropsychiatric disabilities can have a great impact on the rehabilitation from the injury, and overall quality of life.

Alzheimer’s Disease: A Washing Machine on the Fritz

A mathematical model has been developed to numerically model the risk of developing Alzheimer’s disease and Chronic Traumatic Encephalopathy (CTE) as a person ages. The model was programmed in Excel to provide a working prototype computer simulation model. The model provides estimates of the cumulative risk of developing Alzheimer’s disease and CTE as age increases. A one-year step size was used. The model has two major parts: one predicts changes in slow-wave sleep as a person ages and the second component adjusts the flushing efficiency of waste products from the brain. The two components work together and interact to lower the flushing of waste components as age increases. The development of the model provides an overview of how the various factors work together that lead to the onset of Alzheimer’s disease and the associated CTE. Calibration of the coefficients in the model is based on published data sets presented in the literature. Further research and refinement of calibration coefficients should be explored.