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Article: Autoimmune Processes Involved in Organ System Failure Following Infection with SARS-CoV-2.

Kornguth, Steven E / Hawley, Robert J

Advances in experimental medicine and biology

2021 Volume 1318, Page(s) 355–368

Abstract: During the COVID-19 pandemic associated with high incidence, transmissibility, and mortality, this chapter focuses on three phases of the disease: initial exposure, initiation of the immune response to the agent, and finally, an inflammatory/autoimmune- ... ...

Abstract	During the COVID-19 pandemic associated with high incidence, transmissibility, and mortality, this chapter focuses on three phases of the disease: initial exposure, initiation of the immune response to the agent, and finally, an inflammatory/autoimmune-like presentation with pulmonary, neurological, and renal failure and disseminated intravascular coagulation which occurs in a small proportion of the patients. The elegant demonstration of the site of interaction between the spike (S) protein of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is the causative agent of COVID-19, and the ACE (angiotensin-converting enzyme) 2 receptor of cells distributed throughout the body has enabled research efforts to develop pharmacological and immune countermeasures to the viral phase of the disease. This chapter rapidly reviews the molecular and structural organization of SARS-CoV-2 and its interaction with ACE2. It is followed by a discussion over the role of the major histocompatibility complex (MHC) in recognition of the virus. The importance of rapid compartmentation of the viral genome into the target cells as opposed to the binding constant of the virus for the ACE receptor is discussed. Host factors affecting the immune response to the virus are examined, and the subsequent inflammatory dysregulation enabling the cytokine storm leading to system organ failure is described. Finally, the similarities of the clinical effects of the murine hepatitis virus-JHM (a coronavirus) on multi-organ systems (liver, brain, clotting cascade) as described by Perlman and colleagues permit insights regarding the role of the interaction between the host and the virus in developing the clinical presentation of the inflammatory/autoimmune disorders that occur in multiple sclerosis, neuromyelitis optica, and more interestingly, during the third phase of COVID-19.
MeSH term(s)	Animals ; COVID-19 ; Humans ; Lung ; Mice ; Pandemics ; Peptidyl-Dipeptidase A/genetics ; SARS-CoV-2
Chemical Substances	Peptidyl-Dipeptidase A (EC 3.4.15.1)
Language	English
Publishing date	2021-05-10
Publishing country	United States
Document type	Journal Article
ISSN	2214-8019 ; 0065-2598
ISSN (online)	2214-8019
ISSN	0065-2598
DOI	10.1007/978-3-030-63761-3_21
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Cognitive Decline Secondary to Therapeutic Brain Radiation-Similarities and Differences to Traumatic Brain Injury.

Huang, Andrew Jonathan / Kornguth, David / Kornguth, Steven

Brain sciences

2019 Volume 9, Issue 5

Abstract: Traumatic brain injury (TBI) resulting from forceful impacts on the torso and head has been of major interest because of the prevalence of such injuries in military personnel, contact sports and the elderly. Cognitive and behavioral changes associated ... ...

Abstract	Traumatic brain injury (TBI) resulting from forceful impacts on the torso and head has been of major interest because of the prevalence of such injuries in military personnel, contact sports and the elderly. Cognitive and behavioral changes associated with TBI are also seen following whole brain radiation treatment for cancer and chemotherapy for disseminated tumors. The biological mechanisms involved in the initiation of TBI from impact, radiation, and chemotherapy to loss of cognitive function have several shared characteristics including increases in blood brain barrier permeability, blood vessel density, increases in inflammatory and autoimmune responses, alterations in NMDA and glutamate receptor levels and release of proteins normally sequestered in the brain into the blood and spinal fluid. The development of therapeutic agents that mitigate the loss of cognition and development of behavioral disorders in patients experiencing radiation-induced injury may provide benefit to those with TBI when similar processes are involved on a cellular or molecular level. Increased collaborative efforts between the radiation oncology and the neurology and psychiatry communities may be of major benefit for the management of brain injury from varied environmental insults.
Language	English
Publishing date	2019-04-27
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2651993-8
ISSN	2076-3425
ISSN	2076-3425
DOI	10.3390/brainsci9050097
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Article: A Mechanism for the Development of Chronic Traumatic Encephalopathy From Persistent Traumatic Brain Injury.

Demock, Melissa / Kornguth, Steven

Journal of experimental neuroscience

2019 Volume 13, Page(s) 1179069519849935

Abstract: A mechanism that describes the progression of traumatic brain injury (TBI) to end-stage chronic traumatic encephalopathy (CTE) is offered in this article. This mechanism is based upon the observed increase in the concentration of both tau protein and of ... ...

Abstract	A mechanism that describes the progression of traumatic brain injury (TBI) to end-stage chronic traumatic encephalopathy (CTE) is offered in this article. This mechanism is based upon the observed increase in the concentration of both tau protein and of human leukocyte antigen (HLA) class I proteins; the HLA increase is expressed on the cell membrane of neural cells. These events follow the inflammatory responses caused by the repetitive TBI. Associated inflammatory changes include macrophage entry into the brain parenchyma from increased permeability of the blood-brain barrier (BBB) and microglial activation at the base of the sulci. The release of interferon gamma from the microglia and macrophages induces the marked increased expression of HLA class I proteins by the neural cells and subsequent redistribution of the tau proteins to the glial and neuronal surface. In those individuals with highly expressed HLA class I C, the high level of HLA binds tau protein electrostatically. The ionic region of HLA class I C (amino acid positions 50-90) binds to the oppositely charged ionic region of tau (amino acid positions 93-133). These interactions thereby shift the cellular localization of the tau and orient the tau spatially so that the cross-linking sites of tau (275-280 and 306-311) are aligned. This alignment facilitates the cross-linking of tau to form the intracellular and extracellular microfibrils of tau, the primary physiological characteristic of tauopathy. Following endocytosis of the membrane HLA/tau complex, these microfibrils accumulate and produce a tau-storage-like disease. Therefore, tauopathy is the secondary collateral process of brain injury, resulting from the substantial increase in tau and HLA expression on neural cells. This proposed mechanism suggests several potential targets for mitigating the clinical progression of TBI to CTE.
Language	English
Publishing date	2019-05-20
Publishing country	United States
Document type	Journal Article
ZDB-ID	2659991-0
ISSN	1179-0695
ISSN	1179-0695
DOI	10.1177/1179069519849935
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Article: Integration of Biomarkers Into a Signature Profile of Persistent Traumatic Brain Injury Involving Autoimmune Processes Following Water Hammer Injury From Repetitive Head Impacts.

Kornguth, Steven / Rutledge, Neal

Biomarker insights

2018 Volume 13, Page(s) 1177271918808216

Abstract: Objectives: To assemble an algorithm that will describe a "Signature" predictive of an individual's vulnerability to persistent traumatic brain injury (TBI).: Subjects and methods: Studies of athletes and warriors who are subjected to repeated head ... ...

Abstract	Objectives: To assemble an algorithm that will describe a "Signature" predictive of an individual's vulnerability to persistent traumatic brain injury (TBI). Subjects and methods: Studies of athletes and warriors who are subjected to repeated head impacts with rapid acceleration/deceleration forces are used to assist in the diagnosis and management of TBI-affected individuals. Data from multiple areas, including clinical, anatomical, magnetic resonance imaging, cognitive function, and biochemical analyses, are integrated to provide a Signature of persistent TBI. Results: Studies to date indicate that susceptibility to TBI results from an interaction between host genetic and structural vulnerability factors and force and torque of impact on the head and torso. The host factors include molecular markers affecting immune and inflammatory responses to stress/insult as well as anatomical features such as the degree of transcortical fiber projections and vascular malformations. The host response to forceful impact includes the release of intracellular neural proteins and nucleic acids into the cerebrospinal fluid and vascular compartment as well as mobilization of cytokines and macrophages into the central nervous system with subsequent activation of microglia and inflammatory responses including autoimmune processes. Maximum impact to the base of the sulci via a "water hammer effect" is consistent with the localization of microvascular and inflammatory responses in the affected brain region. Conclusions: An assessment of an individuals' predisposition to persistent TBI with delayed cognitive deficits and behavioral changes requires an understanding of host vulnerability (genetic factors and brain structure) and external stressors (force and torque of impact as well as repetitive head injury and time interval between impacts). An algorithm that has utility in predicting vulnerability to TBI will include qualitative and quantitative measures of the host factors weighted against post impact markers of neural injury. Implementation of the resulting "Signature" of vulnerability at early stages of injury will help inform athletes and warriors, along with commanders and management, of the risk/benefit approaches that will markedly diminish health care costs to the nation and suffering to this population. This report attempts to define a strategy to create such an algorithm.
Language	English
Publishing date	2018-10-29
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	2256754-9
ISSN	1177-2719
ISSN	1177-2719
DOI	10.1177/1177271918808216
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Simulation of the Strain Amplification in Sulci Due to Blunt Impact to the Head.

Fagan, Brian T / Satapathy, Sikhanda S / Rutledge, J Neal / Kornguth, Steven E

Frontiers in neurology

2020 Volume 11, Page(s) 998

Abstract: ... chronic traumatic encephalopathy (CTE). Kornguth et al. (1) proposed that an inflammatory and autoimmune process initiated ...

Abstract	Traumatic brain injury (TBI) has become a concern in sports, automobile accidents and combat operations. A better understanding of the mechanics leading to a TBI is required to cope with both the short-term life-threatening effects and long-term effects of TBIs, such as the development chronic traumatic encephalopathy (CTE). Kornguth et al. (1) proposed that an inflammatory and autoimmune process initiated by a water hammer effect at the bases of the sulci of the brain is a mechanism of TBI leading to CTE. A major objective of this study is to investigate whether the water hammer effect is present due to blunt impacts through the use of computational models. Frontal blunt impacts were simulated with 2D finite element models developed to capture the biofidelic geometry of a human head. The models utilized the Arbitrary Lagrangian Eulerian (ALE) method to model a layer of cerebrospinal fluid (CSF) as a deforming fluid allowing for CSF to move in and out of sulci. During the simulated impacts, CSF was not observed to be driven into the sulci during the transient response. However, elevated shear strain levels near the base of the sulci were exhibited. Further, increased shear strain was present when differentiation between white and gray matter was taken into account. Both of the results support clinical observations of (1).
Language	English
Publishing date	2020-09-08
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2564214-5
ISSN	1664-2295
ISSN	1664-2295
DOI	10.3389/fneur.2020.00998
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Article ; Online: Integration of Biomarkers Into a Signature Profile of Persistent Traumatic Brain Injury Involving Autoimmune Processes Following Water Hammer Injury From Repetitive Head Impacts

Steven Kornguth / Neal Rutledge

Biomarker Insights, Vol

2018 Volume 13

Abstract: Objectives: To assemble an algorithm that will describe a “Signature” predictive of an individual’s vulnerability to persistent traumatic brain injury (TBI) Subjects and Methods: Studies of athletes and warriors who are subjected to repeated head impacts ...

Abstract	Objectives: To assemble an algorithm that will describe a “Signature” predictive of an individual’s vulnerability to persistent traumatic brain injury (TBI) Subjects and Methods: Studies of athletes and warriors who are subjected to repeated head impacts with rapid acceleration/deceleration forces are used to assist in the diagnosis and management of TBI-affected individuals. Data from multiple areas, including clinical, anatomical, magnetic resonance imaging, cognitive function, and biochemical analyses, are integrated to provide a Signature of persistent TBI. Results: Studies to date indicate that susceptibility to TBI results from an interaction between host genetic and structural vulnerability factors and force and torque of impact on the head and torso. The host factors include molecular markers affecting immune and inflammatory responses to stress/insult as well as anatomical features such as the degree of transcortical fiber projections and vascular malformations. The host response to forceful impact includes the release of intracellular neural proteins and nucleic acids into the cerebrospinal fluid and vascular compartment as well as mobilization of cytokines and macrophages into the central nervous system with subsequent activation of microglia and inflammatory responses including autoimmune processes. Maximum impact to the base of the sulci via a “water hammer effect” is consistent with the localization of microvascular and inflammatory responses in the affected brain region. Conclusions: An assessment of an individuals’ predisposition to persistent TBI with delayed cognitive deficits and behavioral changes requires an understanding of host vulnerability (genetic factors and brain structure) and external stressors (force and torque of impact as well as repetitive head injury and time interval between impacts). An algorithm that has utility in predicting vulnerability to TBI will include qualitative and quantitative measures of the host factors weighted against post impact markers of neural injury. ...
Keywords	Medicine (General) ; R5-920
Subject code	306
Language	English
Publishing date	2018-10-01T00:00:00Z
Publisher	SAGE Publishing
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Approaches for Monitoring Warfighter Blast-related Exposures in Training to Develop Effective Safety Standards.

Kornguth, Steven / Rylander, Henry G / Smith, Spencer / Campbell, Julia / Steffensen, Steve / Arnold, David / Athey, Alex / Rutledge, J Neal

Military medicine

2021 Volume 186, Issue Suppl 1, Page(s) 515–522

Abstract: Introduction: Traumatic brain injuries are of concern to the sports and military communities because of the age of the participants and costly burden to society. To markedly reduce the impact of traumatic brain injury and its sequela (TBI-S), it is ... ...

Abstract	Introduction: Traumatic brain injuries are of concern to the sports and military communities because of the age of the participants and costly burden to society. To markedly reduce the impact of traumatic brain injury and its sequela (TBI-S), it is necessary to determine the initial vulnerability of individuals as well as identify new technologies that indicate early signs of TBI-S. Materials and methods: Currently, diverse methods have been used by the authors and others in laboratory settings to reveal early signs of persistent TBI-S including simulation modeling of the effect of rapid deceleration on the deviatoric strain (shear force) imposed on specific brain regions, auditory evoked potential (AEP) measurements to determine injury to the auditory cortex optokinetic nystagmus (OKN) measures sensitive to vestibular trauma, and optical coherence tomography (OCT) measures that reveal changes in central visual function obtained noninvasively by examination of the retina. Results: Simulation studies provided technical information on maximal deviatoric strain at the base of the sulci and interface of gray and white matter consistent with results from neuropathology and from magnetic resonance imaging. The AEP and OKN reveal measurable injury to similar regions below the Sylvian fissure including auditory cortex and midbrain, and the OCT reveals changes to the retina consistent with forceful deceleration effects. Conclusions: The studies and results are consistent with prior work demonstrating that noninvasive tests may be sensitive to the presence of TBI-S, potentially in the training field as advances in the portability of test instruments are underway. When combined with baseline data gathered from individuals in quantitative form, key variances can emerge. Therefore, it is hypothesized that AEP, OKN, and OCT, taken together, may yield faster objective and quantitative neurophysiological measures serving as a "signature" of neural injury and more indicative of potentially persistent TBI-S-recommending larger scale longitudinal studies.
MeSH term(s)	Animals ; Brain Concussion ; Brain Injuries, Traumatic/diagnosis ; Humans ; Mice ; Military Personnel ; Reference Standards ; White Matter
Language	English
Publishing date	2021-01-26
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	391061-1
ISSN	1930-613X ; 0026-4075
ISSN (online)	1930-613X
ISSN	0026-4075
DOI	10.1093/milmed/usaa426
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: A Proposed Mechanism for Development of CTE Following Concussive Events: Head Impact, Water Hammer Injury, Neurofilament Release, and Autoimmune Processes.

Kornguth, Steven / Rutledge, Neal / Perlaza, Gabe / Bray, James / Hardin, Allen

Brain sciences

2017 Volume 7, Issue 12

Abstract: During the past decade, there has been an increasing interest in early diagnosis and treatment of traumatic brain injuries (TBI) that lead to chronic traumatic encephalopathy (CTE). The subjects involved range from soldiers exposed to concussive injuries ...

Abstract	During the past decade, there has been an increasing interest in early diagnosis and treatment of traumatic brain injuries (TBI) that lead to chronic traumatic encephalopathy (CTE). The subjects involved range from soldiers exposed to concussive injuries from improvised explosive devices (IEDs) to a significant number of athletes involved in repetitive high force impacts. Although the forces from IEDs are much greater by a magnitude than those from contact sports, the higher frequency associated with contact sports allows for more controlled assessment of the mechanism of action. In our study, we report findings in university-level women soccer athletes followed over a period of four and a half years from accession to graduation. Parameters investigated included T1-, T2-, and susceptibility-weighted magnetic resonance images (SWI), IMPACT (Immediate Post-Concussion Assessment and Cognitive Testing), and C3 Logix behavioral and physiological assessment measures. The MRI Studies show several significant findings: first, a marked increase in the width of sulci in the frontal to occipital cortices; second, an appearance of subtle hemorrhagic changes at the base of the sulci; third was a sustained reduction in total brain volume in several soccer players at a developmental time when brain growth is generally seen. Although all of the athletes successfully completed their college degree and none exhibited long term clinical deficits at the time of graduation, the changes documented by MRI represent a clue to the pathological mechanism following an injury paradigm. The authors propose that our findings and those of prior publications support a mechanism of injury in CTE caused by an autoimmune process associated with the release of neural proteins from nerve cells at the base of the sulcus from a water hammer injury effect. As evidence accumulates to support this hypothesis, there are pharmacological treatment strategies that may be able to mitigate the development of long-term disability from TBI.
Language	English
Publishing date	2017-12-19
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2651993-8
ISSN	2076-3425
ISSN	2076-3425
DOI	10.3390/brainsci7120164
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Book: Neurocognitive and physiological factors during high-tempo operations

Kornguth, Steven E / Steinberg, Rebecca / Matthews, Michael D

(Human factors in defence)

2010

Author's details	edited by Steven Kornguth, Rebecca Steinberg, and Michael D. Matthews
Series title	Human factors in defence
MeSH term(s)	Military Personnel/psychology ; Cognition/physiology ; Stress, Psychological ; Stress, Physiological ; Sleep Deprivation
Language	English
Size	xxiv, 261 p. :, ill. ;, 24 cm.
Publisher	Ashgate
Publishing place	Farnham, Surrey, England ; Burlington, VT
Document type	Book
ISBN	9780754679233 ; 0754679233 ; 9780754698258 ; 0754698254
Database	Catalogue of the US National Library of Medicine (NLM)

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Book ; Online: Neurocognitive and physiological factors during high-tempo operations

Kornguth, Steven E / Matthews, Michael D / Steinberg, Rebecca

(Human Factors in Defence)

2010

Abstract: Neurocognitive and Physiological Factors During High-Tempo Operations features world-renowned scientists conducting groundbreaking research into the basic mechanisms of stress effects on the human body and psyche, as well as introducing novel ... ...

Institution	ebrary, Inc
Author's details	edited by Steven Kornguth, Rebecca Steinberg, & Michael D. Matthews
Series title	Human Factors in Defence
Abstract	Neurocognitive and Physiological Factors During High-Tempo Operations features world-renowned scientists conducting groundbreaking research into the basic mechanisms of stress effects on the human body and psyche, as well as introducing novel pharmaceutics and equipment that can rescue or improve maximal performance during stress. Its focus is on the military model as an exemplar for high-stress environments, the best for understanding human performance under stress, both in the short-term as well as in the long-term. The unprecedented demands on the modern soldier include constantly shifting
MeSH term(s)	Cognition/physiology ; Military Personnel/psychology ; Sleep Deprivation ; Stress, Physiological ; Stress, Psychological
Keywords	Cognition/Physiological aspects ; Combat/Physiological aspects ; Combat/Psychological aspects ; Psychology, Military ; Soldiers/Job stress
Language	English
Size	Online-Ressource (xxiv, 261 p), ill
Publisher	Ashgate
Publishing place	Farnham, Surrey, England ;Burlington, VT
Document type	Book ; Online
Note	Includes bibliographical references and index
ISBN	9780754679233 ; 9780754698258 ; 0754679233 ; 0754698254
Database	Library catalogue of the German National Library of Science and Technology (TIB), Hannover

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