Sage Journals: Discover world-class research

Abstract

Major determinants of the biological background or reserve, such as age, biological sex, comorbidities (diabetes, hypertension, obesity, etc.), and medications (e.g., anticoagulants), are known to affect outcome after traumatic brain injury (TBI). With the unparalleled data richness of coronavirus disease 2019 (COVID-19; ∼375,000 and counting!) as well as the chronic form, long-COVID, also called post-acute sequelae SARS-CoV-2 infection (PASC), publications (∼30,000 and counting) covering virtually every aspect of the diseases, pathomechanisms, biomarkers, disease phases, symptomatology, etc., have provided a unique opportunity to better understand and appreciate the holistic nature of diseases, interconnectivity between organ systems, and importance of biological background in modifying disease trajectories and affecting outcomes. Such a holistic approach is badly needed to better understand TBI-induced conditions in their totality. Here, I briefly review what is known about long-COVID/PASC, its underlying—suspected—pathologies, the pathobiological changes induced by TBI, in other words, the TBI endophenotypes, discuss the intersection of long-COVID/PASC and TBI-induced pathobiologies, and how by considering some of the known factors affecting the person's biological background and the inclusion of mechanistic molecular biomarkers can help to improve the clinical management of TBI patients.

Background and Introduction

Major determinants of the biological background or reserve, such as age,^1–5 biological sex,^6–8 pre-existing conditions (diabetes, hypertension, obesity, etc.),^9,10 and medications (e.g., anticoagulants),^11,12 are known to affect outcome after traumatic brain injury (TBI).

It feels like distant memory, but SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) and its more transmissible variants, Omicron, its subvariants, BA.4 and 5, etc., have infected >100 million persons in the United States and killed >1 million (https://covid.cdc.gov/covid-data-tracker/#datatracker-home) over the past 3 years. Worldwide numbers are ∼700 million infected and ∼7 million killed (https://covid19.who.int). In addition to the tragic loss of lives directly attributable to coronavirus disease 2019 (COVID-19), SARS-CoV-2 infection can cause long-lasting or even permanent pathobiological changes.¹³ “Long-COVID” or post-acute sequelae of SARS-CoV-2 infection (PASC) is a multi-symptomatic condition that involves virtually all organ systems.^14–16 Long-COVID/PASC can adversely affect quality of life and it has become a significant public health challenge.^17–19 It has been shown that long-COVID/PASC can increase one's predisposition to other disorders (e.g., stroke) and adversely affect recovery from various disorders.^16,20

TBI has been long recognized as the “silent epidemic,”^21,22 but given its global nature, it should rather be called a pandemic. However, we still have limited understanding of the biological background, for example, biological sex^23,24 or comorbidities.^25,26 Reflecting the drastic decline in personal mobility attributable to quarantines and lockdowns, the incidence of TBI caused by traffic accidents also declined during the COVID-19 pandemic, but assaults and severe injuries increased.²⁷ Importantly, outcomes were adversely affected, mortality rates increased, especially in middle-/low-income countries.²⁸

The combination of focusing on developing and testing vaccine(s) for SARS-CoV-2 and public healthcare measures, like social distancing, resulted in major disruptions and/or the complete halt of clinical trials,^29–32 including TBI.³³ Compensating for the “lost year(s)” in TBI clinical research attributable to COVID-19 pandemic alone has its own challenges—along with new opportunities.³⁴ The increased recognition of long-COVID/PASC as a public health issue has added a new dimension to an already complex health condition arguing for a reassessment of our previous approaches to TBI. The new, post-COVID-19 patient landscape, the additional varying individual vulnerability attributable to long-COVID/PASC to outcomes after TBI will require further stratification of patients. This can be accomplished by using an extended panel of molecular biomarkers, utilizing machine learning (ML)³⁵ that can guide and optimize individualized therapeutic interventions.

Long-COVID/PASC

The real prevalence of long-COVID/PASC is currently not well known because of different criteria used in reporting.^16,36 The latest Centers for Disease Control and Prevention data indicate that ∼15% of American adults have had long-COVID/PASC and 5.8% of Americans currently have it (https://www.cdc.gov/nchs/covid19/pulse/long-covid.htm). Studies have shown that only ∼10–40% of COVID-19 patients recovered completely 60 days after being discharged from hospitals,^37–39 and the remaining 60–90% of discharged COVID-19 patients have experienced various symptoms that can be attributed only to the infection with SARS-CoV-2.⁴⁰ Although vaccination protects against severe disease, the level of protection against long-COVID/PASC is currently unknown.⁴¹ Importantly, even asymptomatic persons infected with SARS-CoV-2 can develop long-COVID/PASC of varying severity, further complicating one's ability to assess its true prevalence.^42,43 The majority (∼90%) of severely ill COVIID-19 patients have reported long-COVID/PASC symptomatology,⁴⁴ but up to 40% of patients after a mild case of COVID-19 infection have also reported long-COVID/PASC-like symptoms.^13,45

Although some studies indicated that long-COVID/PASC is relatively independent of the severity of COVID-19,⁴⁶ there is a correlation between disease severity and prevalence of long-COVID-PASC. A Swedish study showed that only 1% of mild COVID-19 patients developed long-COVID/PASC, but 32% of severe cases (intensive care unit–treated persons) showed symptoms 1 year post-infection.⁴⁷ Biological sex also plays an important role; severe COVID-19 with unfavorable outcome mainly affects males, whereas long-COVID/PASC disproportionally affects biological females.^47–50

Long-COVID/PASC can affect multiple organ systems, and the most frequently reported symptoms are fatigue, shortness of breath, nausea, palpitations, joint and chest pain, and gastrointestinal and gynecological problems.^15,40 Most patients, however, suffer from neurological and -psychiatric symptoms such as “brain fog,” anxiety/depression, memory loss, inattention, disorientation, disturbances of sleep, and headaches.^14,51–57 These symptoms are similar to a previously described condition, functional neurological disorders (FNDs),⁵⁸ and similar symptoms were observed after SARS and MERS infections.⁵⁹ Patients with chronic fatigue syndrome and fibromyalgia⁶⁰ as well as post-traumatic stress disorder⁶¹ and “chronic” TBI/persistent post-concussive syndromes also have a similar symptomatology.⁶² It should also be noted that many of these symptoms can be psychogenic, caused by the emotional, mental, and psychological stress attributable to COVID-19-related shutdowns, quarantines, social isolations, etc. Such a lack of specificity and complexity make diagnosing “organic” long-COVID/PASC both important and challenging. A recent study has found evidence that even vaccination without infection can cause FNDs,⁶³ but it is unclear whether the cause is organic or “psychogenic.”

Candidate Pathomechanism(s) of Long-COVID/PASC

The exact pathomechanism of long-COVID/PASC is currently not known. Candidate mechanisms (summarized in Table 1) fell into two categories: direct and indirect.^64–66

Table 1.

List of Pathomechanisms Suspected in the Development of Long-COVID/PASC and Their Potential Effect on the Outcome After Various Severities of TBI

Pathomechanism(s) (selected)	Level of evidence in the pathomechanism of long-COVID/PASC	Potential influence/effect on outcome after
Pathomechanism(s) (selected)		miTBI	MoTBI	sTBI
Direct
Direct viral invasion and/or viral reservoirs in the CNS	Low/uncertain^{67,68,244,245}	?	?	?
Definition: presence of the virus and/or viral particles in cells of the CNS	Low/uncertain^{67,68,244,245}	?	?	?
Indirect
Endothelial damage/dysfunction/(micro)vascular injury	Moderate to high^{64,70,75–77,93}	+++	+++	+++
Definition: abnormal vascular functions, more reactive endothelial phenotype, injury, blockage of small vessels including capillaries	Moderate to high^{64,70,75–77,93}	+++	+++	+++
Abnormal coagulation	High (after severe COVID-19)^79,246,247	+++	+++	+++
Definition: disruptions in the body's ability to control blood clotting	High (after severe COVID-19)^79,246,247	+++	+++	+++
Inflammation	High (after severe COVID-19)^{81,89,107,248–250}	+/–	++	+++
Definition: maladaptive immune response	High (after severe COVID-19)^{81,89,107,248–250}	+/–	++	+++
Abnormal immunometabolism	Moderate^84–87,251	+/–	++	+++
Definition: changes in intracellular metabolic pathways of immune cells that alter their functionality	Moderate^84–87,251	+/–	++	+++

PASC, post-acute sequelae of SARS-CoV-2 infection; TBI, traumatic brain injury; CNS, central nervous system; COVID-19, coronavirus disease 19.

Direct mechanisms

Direct mechanism includes, viral invasion, proliferation, and effect of viral particles (e.g., viral proteins) on the various cell types of the brain.^67–69 There is in vitro evidence that SARS-CoV-2 can infect cultured human cerebral microvascular endothelial cells.⁷⁰ Viral particles were found in endothelial cells in SARS-CoV-2-infected non-human primates, and SARS-CoV-2 nucleic acids were detected in supporting cells, choroid plexus, and sustentacular cells, but not in neurons.⁷¹ It is possible that some, likely immunocompromised persons may have a hidden viral reservoir, which can cause reinfection. Recurrence of SARS-CoV-2 positivity after antiviral treatment by Paxlovid or other SARS-CoV-2 antivirals demonstrates that there can be an undetectably low level of a viral reservoir that can cause COVID-19 to rebound.⁷² Based on our current understanding and available evidence, the hidden cerebral viral reservoir likely exists in only a small subset of long-COVID/PASC patients⁷³ and may not be responsible for the majority of long-COVID/PASC cases.⁷⁴

Indirect mechanisms

The indirect mechanism includes endothelial/vascular damage,^70,75–78 coagulopathy,^79,80 and abnormal immune functions like altered immunometabolism, chronic inflammation, immune exhaustion, and autoimmunity.^54,81–90

Endothelial pathologies

Endothelial damage/dysfunction/(micro)vascular injury has emerged as a leading candidate pathology of long-COVID/PASC.^78,91,92 The main target of SARS-CoV-2 is the ACE2 receptor bearing endothelial cells in the central nervous system (CNS),^70,71 and the vascular dysfunction, endothelial damage, and (micro)vascular injury resulting in dysfunction of blood vessels has been one of the hallmarks of systemic SARS-CoV-2 infection and one of the leading candidate pathomechanisms of long-COVID/PASC.^{75–77,93–96} Endothelial cells are key regulators of cell-to-cell adhesion, blood–brain barrier (BBB) formation, and transendothelial transport, including cell migration, coagulation, and inflammation, involving both humoral and cellular pathways.⁷⁶ Endothelial stress caused by SARS-CoV-2 infection can cause long-lasting changes in the cerebral microvasculature in the forms of microthrombosis and altered BBB functions.^97–100 In summary, endothelial and (micro)vascular abnormalities appear to be the leading pathomechanisms classifying long-COVID/PASC as a new vessel disease.⁷⁸

Coagulopathies

Endothelial/vascular stress and damage can lead to coagulopathies and persistent hyper- and abnormal coagulation, one of the hallmarks of acute COVID-19,¹⁰¹ but studies have also demonstrated the persistence of coagulopathies in long-COVIC/PASC.^102,103 The presence of microclots with abnormal protein content, including amyloid, combined with an abnormal fibrinolytic system unable to resolve these clots, can result in a hypercoagulable state, manifested in the circulation of microclots.^103,104 Studies have hypothesized that this hypercoagulable state is caused by a chronic inflammatory process^104,105 linking vascular abnormalities and the hypercoagulable state to various forms of immune pathologies.^46,105,106

Inflammation

The severe form of COVID-19 infection is characterized by a hyperinflammation “cytokine storm,” which can lead to a chronically altered, maladaptive immune response.^81,107 The cytokine storm, the hallmark of severe COVID-19, causes—additional—organ damage, the release of damage-associated molecular patterns (DAMPs).¹⁰⁸ HMGB1, hsp70, mitochondrial DNA, and other DAMPs further activate the inflammatory process, leading to a vicious cycle that, if not completely broken, can exist for months after the acute phase and lead to long-COVID/PASC.^109,110 Indeed, an altered immune system, characterized by chronically elevated levels of proinflammatory molecules, has been identified as one of the leading molecular pathologies of long-COVID/PASC.^111,112 Circulating proinflammatory molecules can cause—additional—vascular stress and endothelial activation, leading to fibrinogen accumulation around the vessels, attracting microglia and/or macrophages and inducing a vicious cycle of neuroinflammation and tissue damage in the CNS.^113,114 Another form of immune pathologies suspected in the pathology of long-COVID/PASC is altered immunometabolism.⁸⁶ SARS-CoV-2 infection can modify any of the six major metabolic processes that compromise their functionality, leading/contributing to a chronic inflammatory stage.^84,85,87

Autoimmunity

Autoimmunity in long-COVID/PASC

Immunedysregu-lation, especially autoimmunity, has been increasingly recognized as one or the main pathologies responsible for long-COVID/PASC.^83,115,116 Several studies have indicated that SAR- CoV-2 infection can result in an unbalance of the affected person's immune homeostasis, resulting in the development of autoantibodies potentially leading to the development autoimmune diseases.^116–118 Autoantibodies against brain-tissue–specific epitopes have been found in long-COVID/PASC patients, and their presence correlates with neuropsychiatric abnormalities.¹¹⁹ During the acute phase of SARS-CoV-2 infection, serum levels of neural injury markers of GFAP and NF-L were elevated and, importantly, remained elevated in patients who could be classified as suffering from long-COVID/PASC.^120–122 Elevated levels of neural injury markers were associated with elevated levels of inflammatory cytokines and IgM autoantibodies against, for example, myelin-associated glycoprotein and many other brain-specific proteins.^119,123 Abnormal protein homeostasis, combined with protease activation and hyperinflammation, can significantly contribute to the autoimmune mechanism,^124,125 the generation of autoantibodies against brain-specific proteins.^16,115,126

In summary, current evidence points toward three major inter-related pathomechanisms (vascular/endothelial stress/damage, abnormal coagulation, and inflammation) that are the most likely underlying pathologies of long-COVID/PASC. Some of these pathomechanisms may occur individually, but they can also overlap, and can also change over time.

TBI: A Spectrum of Disorders of Different Disease Endophenotypes

TBI is not a single disease, but a spectrum of disorders with the same causation: physical insult to the head and brain.^127–132 The only similarity between an unconscious patient with skull fracture, subdural hematoma, and brain contusion and a patient walking into an emergency room with a bump on his or her head feeling dizzy is that there was a physical impact—of different intensities and kinds—to the head.¹³³ Thus, there are two dimensions of TBI that need to be considered; one is severity, traditionally addressed by the Glasgow Coma Scale introduced in 1974 by Teasdale and Jennett.¹³⁴ However, our biological understanding of the pathophysiological mechanisms underlying the functional abnormalities have become substantially more refined since 1974.^135–138 Mild TBI, clinically also called concussion, only causes temporary perturbance of cellular structures and may dislocate membrane-bound ion channels, receptors, and/or intracellular organelles, causing typically transient molecular disturbances reflected in metabolic abnormalities that clinically manifest as a temporary altered state of consciousness.^139,140 After moderate TBI, biomechanical forces cause substantial direct tissue and cell damage and cell death, majorly disrupting neuronal signaling and networks manifesting clinically as prolonged loss of consciousness.¹⁴¹ Severe TBI, frequently comorbid with polytrauma, causes major loss of brain parenchyma, severe disruption of neuronal networks, loss of consciousness, and severe neurological dysfunctionality.^142–145

The second critical dimension is the temporal aspect of TBI-induced pathobiological changes.¹⁴⁶ Though the exact temporal profile of these changes is currently not well understood, available data indicate a dynamic and complex pattern of TBI-induced pathobiological changes that can span weeks or months.^147–153

Major Pathobiologies Triggered by TBI: The Disease Endophenotypes

The physical impact to the head—depending on the intensity and type of injury—triggers a variety of pathobiological changes that can occur in partly overlapping fashion, interact in a highly complex fashion, and change over time.^154,155 Penetrating TBI causes massive tissue damage, cellular death, and bleeding that release intracellular molecules called damage-associated molecules (DAMPs). DAMPs, like HMGB1, mitochondrial DNA, and S1008/9, rapidly activate the innate immune system by Toll-like receptors (TLRs) with the aim to remove tissue debris and restore homeostasis.^156,157 However, the inflammatory process can continue beyond the acute phase and transform into a chronic process.¹⁵⁸

Axonal injury is a hallmark of diffuse TBI, but the extent of damage varies from major white matter loss clinically manifested in severe functional deficits to temporary, molecular-level disruption of axonal structures, causing mild and transient neurobehavioral abnormalities.^159–162

An important but currently poorly understood TBI (endo)phenotype is characterized by injury to the cerebral vasculature.^163–166 The effect of diffuse TBI on the vasculature can range from endothelial stress, damaged BBB function, microbleeding, and hemorrhage.^167–169 These pathobiological changes have been detected by neuroimaging^163,170 and also by elevated plasma levels of protein biomarkers of endothelial and vascular stress and damage (VEGF, vWF, and cFN)^{163,166,171–175} and/or endothelial tight junction proteins (Claudin-5 and Occludin).^150,176,177 These TBI-induced vascular changes are important inducers of downstream mechanisms such as activation of blood clotting and the innate immune system.^178–183 Inflammation is a key adaptive response to any kind of noxious stimuli in all multi-cellular organisms,^184,185 and the neuroinflammatory response to TBI—including mild, especially repeated mTBI—is emerging as a key pathobiology responsible for adverse outcomes.^183,186,187 The neuroinflammatory response to TBI includes both humoral and cellular players.¹⁸³ Depending on the type (e.g., closed, diffuse, or penetrating) and severity of the injury, the cellular components can include only intracranial cellular population, microglia, and astroglia or, after penetrating injury, peripheral immune cells (e.g., macrophages also contribute to the inflammatory response).¹⁸⁸

Astrocytes play an especially important and complex role in the neuroinflammatory process; they are involved in regulating both innate and adaptive immune responses after TBI.^189–191 In the activation of astrocytes, astrogliosis subsequent to penetrating TBI demarcates the injury site and a highly complex bidirectional signaling process between astrocytes and microglia is a key regulator of the acute and chronic neuroinflammatory response.^189–191 Moderate and severe TBI disrupt—to varying degrees—the BBB causing the exposure of brain-specific molecules to the adaptive immune system, generating potentially detrimental long-lasting cellular and humoral responses that can cause or contribute to chronic adverse conditions.^183,192,193

Intersection of Long-COVID/PASC and TBI-Induced Pathobiologies

Several of the suspected pathobiologies underlying long-COVID/PASC have the potential to affect recovery after various forms of TBI (Table 1). A major challenge for the clinical management of TBI patients has long been the heterogeneity of patients differing, for example, in age, biological sex, comorbidities, comedications, and cofactors—such as alcohol and/or drugs—and pre-existing conditions, such as long-COVID/PASC. The outcome after SARS-CoV-2 infection, especially after the severe form, has shown a sharp age dependence; elderly persons have shown significantly poorer outcome,^194,195 but older age as a risk factor for developing long-COVID/PASC has been questioned.¹⁹⁶ Conversely, young age has been shown as “protective” against the severe form of COVID-19,¹⁹⁴ but not against developing long-COVID/PASC.^197,198 Pediatric and adolescent populations represent a significant percentage of TBI cases,¹⁹⁹ and it is known that TBI adversely affects later phases of neuronal development.^4,200–203 The question is of what unknown is the effect of SARS-CoV-2 infection and/or long-COVID/PASC on the outcome of TBI, specifically the mild/concussive form that is the most frequent among adolescents/young adults. Elderly persons, representing the other predominant age group in TBI, has especially poor recovery after TBI, as reported by the large TRACK-TBI study,⁸ and long-COVID/PASC can further diminish the recovery process.

Biological sex seems to play a significant role in outcome after SARS-CoV-2 infections. Severe COVID-19 with an unfavorable outcome was observed mainly in males, whereas long-COVID/PASC disproportionally affected biological females.^47–50 The large TRACK-TBI study has found that women are more vulnerable to develop persistent neurobehavioral symptoms than men after mTBI and suffer from chronic post-concussion syndromes.⁸ Accordingly, women suffering from long-COVID/PASC will likely have poorer long-term functional outcomes after TBI.

There are currently very limited data on how long the long-COVID/PASC really lasts and whether it has distinct disease phases.⁴⁵ The current view is that long-COVID/PASC is a chronic condition with relatively steady pathobiologies,^15,103 but there are reports indicating time-dependent changes in the underlying pathobiologies.⁴⁴ TBI induces severity- and injury-type–dependent pathobiological responses that change dynamically over time, although the exact temporal pattern of these changes is currently poorly understood.^{153,182,193,204} Accordingly, not all the pathologies are present at every post-injury period,^{148,150–152} and their co-occurrence with pathologies of long-COVID/PASC—especially an abnormal inflammatory profile—has the potential to negatively affect the recovery process. SARS-CoV-2 infection itself can cause brain injury—defined as elevated serum levels of brain-injury markers NF-L, Tau, and GFAP—during the acute phase of COVID-19.¹²²

Elevated levels of these brain injury biomarkers were associated with elevated serum levels of inflammatory cytokines (TNFa, IL-1b, and IL-6) and autoantibodies—both IgM and IgG—against brain-specific proteins (e.g., myelin-associated glycoprotein). Importantly, 4 months after the infection, the convalescent phase that can qualify for long-COVID/PASC, serum levels of brain injury markers, especially Tau, were still significantly elevated over normal controls along with inflammatory cytokines and autoantibodies. These findings implicate an ongoing inflammatory and autoimmune process, given that manifestations of immune dysregulation, one of the main pathomechanisms of SARS-CoV-2 infection, are also suspected in causing long-COVID/PASC.^83,118,205

The altered biological background in long-COVID/PASC characterized by vascular abnormalities and, importantly, by a chronic inflammatory landscape can majorly affect the disease process after TBI (Fig. 1). An ongoing neuroinflammation has been proposed as the key pathomechanism of chronic TBI and TBI-induced pathological processes (e.g., chronic traumatic encephalopathy and Alzheimer's disease).^191,206 Additional parenchymal damage caused by TBI will take place on an already dysregulated immune system causing additional and/or maintaining the long-term parenchymal damage, releasing DAMPs, further activating the adaptive immune response through TLR signaling and resulting in a vicious cycle that delays and or adversely affects the recovery process after TBI.^120,122

FIG. 1.

Onset and extent of major pathobiological changes during the various phases of severe COVID-19 and the hypothesized role of long-COVID/PASC affecting the outcome of TBI. The pathobiological changes identified or suspected during the acute, subacute, and chronic (long-COVID/PASC) phases of COVID-19 are listed. The dashed turquoise line indicates the relative intensity and relative timeline of pathobiologies of COVID-19. The solid turquoise line indicates the relative intensities of pathobiological changes associated with long-COVID/PASC. The solid yellow curve indicates the relative intensity and temporal changes of pathobiologies of TBI on a long-COVID/PASC background. Relevant references are in the text and listed in the references. DAMPs, damage-associated molecular patterns; PASC, post-acute sequelae SARS-CoV-2 infection; TBI, traumatic brain injury.

The Role of Biomarkers

Identification of TBI endophenotypes is a critical step toward developing evidence-based individualized clinical management of TBI patients.^{166,207–209} Because of their rich information content, blood-based (and other biofluid) protein biomarkers have currently the most potential to perform molecular phenotyping of TBI patients.^210–214 In order to identify increased vulnerability of TBI patients attributable to pathologies underlying/suspected in long-COVID/PASC, an expanded biomarker panel should be used. Such a panel should include markers of any of the pathomechanisms suspected in the development of long-COVID/PASC (Table 2). These markers should be in addition and used in the context of the current, most commonly used, well-established markers of neural injury (GFAP, UCH-L1, Tau, and NF-L).²¹¹ There is an increasing recognition to use “mechanistic” biomarkers in TBI in conjunction with “classical” injury markers.²¹⁵ However, markers of coagulopathies (e.g., vWF, D-dimer), endothelial stress (e.g., VEGF-A, Ang-1/2, and ET-1), vascular damage (CLDN5, Occludin, VCAM-1, and cFN),^{166,174,216—220} and inflammation (e.g., CRF, IL-1b, IL-6, TNFa, IL-8, and CXCL12)^84,221—223 that have already been used in clinical settings should be coanalyzed with the panel of injury markers. The caveat is that elevated serum levels of the neural injury marker NF-L have been found in patients who could qualify as suffering from long-COVID/PASC (4 months after infection). This finding indicates an ongoing neuronal damage likely caused by an ongoing inflammation.^120–122

Table 2.

Biomarkers of Selected Pathomechanisms Suspected in PASC for Blood-Borne Phenotyping of TBI Patients

Biomarker of	Full name, abbreviation, references, and notes
Autoimmunity	Cyclic citrullinated peptide (CCP),²⁵² protein microarray-based assays^253,254
Abnormal immune response; altered immunometabolism, immune dysregulation, hyperinflammation	Chemerin (ChM)^84,221,222
	C-reactive peptide (CRP), tumor necrosis factor alpha (TNF-a), interleukin-1 beta (IL-1b), interleukin-6 (IL-6)²²³
Endothelial (vascular) damage, abnormal coagulation	von Willebrand factor (vWF), IL-18, vascular endothelial growth factor (VEGF), cellular fibronectin (cFN), D-dimer (Dd), fibrinogen (Fb)^{166,174,216–220}

PASC, post-acute sequelae of SARS-CoV-2 infection; TBI, traumatic brain injury.

The major challenge will be how to analyze, harmonize, and correlate the large volume of—various—biomarker data in order to help clinical decision making. Potential solutions should include massive use of Big Data approaches like ML.^35,207,224 Critically, any successful ML approach critically relies on a high quality and high quantity of primary-protein, physiology, imaging, etc., biomarker data and well-structured/machine-readable clinical reports.^35,225–227

The critical unmet need is the availability of normal, reference ranges of biofluid blood—plasma and serum—and cerebrospinal fluid–based protein biomarkers. Astonishingly, no such publicly available database exists. Combined with issues of pre-analytical and analytical variables (e.g., different assay platforms),²²⁸ the current use of biomarker data has limited value.

The Role of TBI Models

Pioneering works have developed high-fidelity animal models of various forms of TBI,^229–234 enabling one to identify the anatomical, cellular, and molecular substrates of the primary and secondary injury processes.^{185,235–237} These experiments have—mostly if not exclusively—been performed using healthy young male rats and only recently females have also been included.^238,239 Though studies have started to address how the young, developing brain responds to and recovers from TBI,²⁴⁰ much less is known about the aging brain's response²⁴¹ despite the huge and increasing number of aging persons affected by TBI.²⁴² These elderly patients frequently suffer from comorbidities (e.g., long-COVID/PASC) and under (multiple) medications that combined can substantially alter patients' biological background in addition to age.^26,243 In order to generate clinically relevant, translatable information, there is a need to develop and use animal models of human conditions/diseases (e.g., chronic inflammation) that are prevalent in the aged population.

Summary

Long-COVID/PASC has been identified as a significant public health issue. It reduces the quality of life, increases the vulnerability of affected persons to other diseases, and negatively affects disease processes. The underlying—suspected—pathologies, vascular abnormalities, coagulopathies, and inflammation can adversely affect the recovery process after TBI. Expanded diagnostics aimed to better inform about the biological background and comorbidities, such as long-COVID/PASC, of TBI patients will help to develop individualized clinical management.

Footnotes

Acknowledgments

The opinions or assertions contained herein are those of the author and are not to be construed as official or reflecting the views of the Department of Defense, Department of the Navy, or Uniformed Services University.

Funding Information

No funding was received for this work.

Author Disclosure Statement

No competing financial interests exist.

Abbreviations Used

References

Karr

, Iverson

, Berghem

, et al. Complicated mild traumatic brain injury in older adults: post-concussion symptoms and functional outcome at one week post injury. Brain Inj, 2020; 34(1):26–33; doi: 10.1080/02699052.2019.1669825

Levin

, Pershina

, Bugaev-Makarovskiy

, et al. Why do levels of anti-inflammatory cytokines increase during memory acquisition?. Neuroscience, 2021; 473:159–169; doi: 10.1016/j.neuroscience.2021.08.007

dell'Aquila

, Maiese

, De Matteis

, et al. Traumatic brain injury: estimate of the age of the injury based on neuroinflammation, endothelial activation markers and adhesion molecules. Histol Histopathol, 2021; 36(8):795–806; doi: 10.14670/hh-18-319

Delage

, Taib

, Mamma

, et al. Traumatic brain injury: an age-dependent view of post-traumatic neuroinflammation and its treatment. Pharmaceutics, 2021; 13(10):1624; doi: 10.3390/pharmaceutics13101624

Kim

, Chelluboina

, Chokkalla

, et al. Age and sex differences in the pathophysiology of acute CNS injury. Neurochem Int, 2019; 127:22–28; doi: 10.1016/j.neuint.2019.01.012

Biegon

Considering biological sex in traumatic brain injury. Front Neurol, 2021; 12:576366; doi: 10.3389/fneur.2021.576366

Krukowski

Short review: The impact of sex on neuroimmune and cognitive outcomes after traumatic brain injury. Brain Behav Immun Health, 2021; 16:100327; doi: 10.1016/j.bbih.2021.100327

Levin

, Temkin

, Barber

, et al. Association of sex and age with mild traumatic brain injury-related symptoms: a TRACK-TBI study. JAMA Netw Open, 2021; 4(4):e213046; doi: 10.1001/jamanetworkopen.2021.3046

Saunders

, Selassie

, Hill

, et al. Pre-existing health conditions and repeat traumatic brain injury. Arch Phys Med Rehabil, 2009; 90(11):1853–1859; doi: 10.1016/j.apmr.2009.05.020

10.

Dell

, Grossner

, Staph

, et al. A population-based study of pre-existing health conditions in traumatic brain injury. Neurotrauma Rep, 2021; 2(1):255–269; doi: 10.1089/neur.2020.0065

11.

Spano

, 2nd, Shaikh

, Boneva

, et al. Anticoagulant chemoprophylaxis in patients with traumatic brain injuries: a systematic review. J Trauma Acute Care Surg, 2020; 88(3):454–460; doi: 10.1097/ta.0000000000002580

12.

Wiegele

, Schöchl

, Haushofer

, et al. Diagnostic and therapeutic approach in adult patients with traumatic brain injury receiving oral anticoagulant therapy: an Austrian interdisciplinary consensus statement. Crit Care, 2019; 23(1):62; doi: 10.1186/s13054-019-2352-6

13.

Garg

, Maralakunte

, Garg

, et al. The conundrum of ‘long-COVID-19’: a narrative review. Int J Gen Med, 2021; 14:2491–2506; doi: 10.2147/ijgm.S316708

14.

Al-Hakeim

, Al-Rubaye

, Al-Hadrawi

, et al. Long-COVID post-viral chronic fatigue and affective symptoms are associated with oxidative damage, lowered antioxidant defenses and inflammation: a proof of concept and mechanism study. Mol Psychiatry, 2023; 28(2):564–578; doi: 10.1038/s41380-022-01836-9

15.

Proal

, VanElzakker

. Long COVID or post-acute sequelae of COVID-19 (PASC): an overview of biological factors that may contribute to persistent symptoms. Front Microbiol, 2021; 12:698169; doi: 10.3389/fmicb.2021.698169

16.

Davis

, McCorkell

, Vogel

, et al. Long COVID: major findings, mechanisms and recommendations. Nat Rev Microbiol, 2023; 21(3):133–146; doi: 10.1038/s41579-022-00846-2

17.

Pye

, Roberts

, Blennerhassett

, et al. A public health approach to estimating the need for long COVID services. J Public Health (Oxf), 2023; 45(1):169–175; doi: 10.1093/pubmed/fdab365

18.

Nittas

, Gao

, West

, et al. Long COVID through a public health lens: an umbrella review. Public Health Rev, 2022; 43:1604501; doi: 10.3389/phrs.2022.1604501

19.

Facing up to long COVID. Lancet 2020;396(10266):1861; doi: 10.1016/s0140-6736(20)32662-3

20.

Merkler

, Parikh

, Mir

, et al. Risk of ischemic stroke in patients with coronavirus disease 2019 (COVID-19) vs patients with influenza. JAMA Neurol, 2020; 77(11):1–7; doi: 10.1001/jamaneurol.2020.2730

21.

Goldstein

Traumatic brain injury: a silent epidemic. Ann Neurol, 1990; 27(3):327; doi: 10.1002/ana.410270315

22.

Pascrell

Jr . Traumatic brain injury: the silent epidemic. N J Med, 2001; 98(11):47–48.

23.

Hanafy

, Amodio

, Haag

, et al. Is it prime time for sex and gender considerations in traumatic brain injury? Perspectives of rehabilitation care professionals. Disabil Rehabil, 2022; 44(5):684–692; doi: 10.1080/09638288.2020.1774670

24.

Mollayeva

, Bordignon

, Ishtiaq

, et al. Knowledge of sex and gender and related information needs in patients with traumatic brain injury: in-depth interview study. Disabil Rehabil, 2021; 43(13):1872–1882; doi: 10.1080/09638288.2019.1683235

25.

Hanafy

, Xiong

, Chan

, et al. Comorbidity in traumatic brain injury and functional outcomes: a systematic review. Eur J Phys Rehabil Med, 2021; 57(4):535–550; doi: 10.23736/s1973-9087.21.06491-1

26.

Maas

AIR

, Menon

, Manley

, et al. Traumatic brain injury: progress and challenges in prevention, clinical care, and research. Lancet Neurol, 2022; 21(11):1004–1060; doi: 10.1016/s1474-4422(22)00309-x

27.

Rajalu

, Indira Devi

, Shukla

, et al. Traumatic brain injury during COVID-19 pandemic-time-series analysis of a natural experiment. BMJ Open, 2022; 12(4):e052639; doi: 10.1136/bmjopen-2021-052639

28.

Damara

, Muchamad

, Anton

, et al. Epidemiological pattern of traumatic brain injury in the COVID-19 pandemic: a systematic review and meta-analysis. World Neurosurg, 2022; 161:e698–e709; doi: 10.1016/j.wneu.2022.02.081

29.

Sathian

, Asim

, Banerjee

, et al. Impact of COVID-19 on clinical trials and clinical research: a systematic review. Nepal J Epidemiol, 2020; 10(3):878–887; doi: 10.3126/nje.v10i3.31622

30.

Miller

, Williams

COVID-19's Impact on Clinical Research. In: RTI Press Research Brief. RTI Press: Research Triangle Park, NC; 2014.

31.

Teng

, Wang

, Yang

, et al. The impact of COVID-19 on clinical outcomes in people undergoing neurosurgery: a systematic review and meta-analysis. Syst Rev, 2023; 12(1):137; doi: 10.1186/s13643-023-02291-5

32.

van Dorn

COVID-19 and readjusting clinical trials. Lancet, 2020; 396(10250):523–524; doi: 10.1016/s0140-6736(20)31787-6

33.

Lester

, Leach

, Zaben

. The impact of the COVID-19 pandemic on traumatic brain injury management: lessons learned over the first year. World Neurosurg, 2021; 156:28–32; doi: 10.1016/j.wneu.2021.09.030

34.

Agoston

DV.

COVID-19 and traumatic brain injury (TBI); what we can learn from the viral pandemic to better understand the biology of TBI, improve diagnostics and develop evidence-based treatments. Front Neurol, 2021; 12:752937; doi: 10.3389/fneur.2021.752937

35.

Agoston

DV.

Big Data, Artificial Intelligence and Machine Learning in Neurotrauma. In: Leveraging Biomedical and Healthcare Data: Semantics, Analytics and Knowledge. ( Kobeissy

, Alawieh

, Zaraket

, Wang

ed.) Academic Press: London; 2019; pp. 53–75.

36.

Perlis

, Santillana

, Ognyanova

, et al. Prevalence and correlates of long COVID symptoms among US adults. JAMA Netw Open, 2022; 5(10):e2238804; doi: 10.1001/jamanetworkopen.2022.38804

37.

Chen

, Haupert

, Zimmermann

, et al. Global prevalence of post COVID-19 condition or long COVID: a meta-analysis and systematic review. J Infect Dis, 2022; 226(9):1593–1607; doi: 10.1093/infdis/jiac136

38.

Lopez-Leon

, Wegman-Ostrosky

, Ayuzo Del Valle

, et al. Long-COVID in children and adolescents: a systematic review and meta-analyses. Sci Rep, 2022; 12(1):9950; doi: 10.1038/s41598-022-13495-5

39.

Sugiyama

, Miwata

, Kitahara

, et al. Long COVID occurrence in COVID-19 survivors. Sci Rep, 2022; 12(1):6039; doi: 10.1038/s41598-022-10051-z

40.

Nalbandian

, Sehgal

, Gupta

, et al. Post-acute COVID-19 syndrome. Nat Med, 2021; 27(4):601–615; doi: 10.1038/s41591-021-01283-z

41.

Wisnivesky

, Govindarajulu

, Bagiella

, et al. Association of vaccination with the persistence of post-COVID symptoms. J Gen Intern Med, 2022; 37(7):1748–1753; doi: 10.1007/s11606-022-07465-w

42.

Scherlinger

, Pijnenburg

, Chatelus

, et al. Effect of SARS-CoV-2 vaccination on symptoms from post-acute sequelae of COVID-19: results from the nationwide VAXILONG Study. Vaccines (Basel), 2021; 10(1):46; doi: 10.3390/vaccines10010046

43.

Wynberg

, Han

, Boyd

, et al. The effect of SARS-CoV-2 vaccination on post-acute sequelae of COVID-19 (PASC): a prospective cohort study. Vaccine, 2022; 40(32):4424–4431; doi: 10.1016/j.vaccine.2022.05.090

44.

, Yuan

, Chen

, et al. Multiple early factors anticipate post-acute COVID-19 sequelae. Cell, 2022; 185(5):881–895.e20; doi: 10.1016/j.cell.2022.01.014

45.

Taquet

, Dercon

, Luciano

, et al. Incidence, co-occurrence, and evolution of long-COVID features: a 6-month retrospective cohort study of 273,618 survivors of COVID-19. PLoS Med, 2021; 18(9):e1003773; doi: 10.1371/journal.pmed.1003773

46.

Ramakrishnan

, Kashour

, Hamid

, et al. Unraveling the mystery surrounding post-acute sequelae of COVID-19. Front Immunol, 2021; 12:686029; doi: 10.3389/fimmu.2021.686029

47.

Hedberg

, Granath

, Bruchfeld

, et al. Post COVID-19 condition diagnosis: a population-based cohort study of occurrence, associated factors, and healthcare use by severity of acute infection. J Intern Med, 2023 Feb;293(2):246–258; doi: 10.1111/joim.13584

48.

Sylvester

, Rusu

, Chan

, et al. Sex differences in sequelae from COVID-19 infection and in long COVID syndrome: a review. Curr Med Res Opin, 2022; 38(8):1391–1399; doi: 10.1080/03007995.2022.2081454

49.

Pelà

, Goldoni

, Solinas

, et al. Sex-related differences in long-COVID-19 syndrome. J Womens Health (Larchmt), 2022; 31(5):620–630; doi: 10.1089/jwh.2021.0411

50.

Fernández-de-Las-Peñas

, Martín-Guerrero

, Pellicer-Valero ÓJ, et al. Female sex is a risk factor associated with long-term post-COVID related-symptoms but not with COVID-19 Symptoms: the LONG-COVID-EXP-CM Multicenter Study. J Clin Med, 2022; 11(2):413; doi: 10.3390/jcm11020413

51.

Stefanou

, Palaiodimou

, Bakola

, et al. Neurological manifestations of long-COVID syndrome: a narrative review. Ther Adv Chronic Dis, 2022; 13:20406223221076890; doi: 10.1177/20406223221076890

52.

Mehandru

, Merad

. Pathological sequelae of long-haul COVID. Nat Immunol, 2022; 23(2):194–202; doi: 10.1038/s41590-021-01104-y

53.

Aiyegbusi

, Hughes

, Turner

, et al. Symptoms, complications and management of long COVID: a review. J R Soc Med, 2021; 114(9):428–442; doi: 10.1177/01410768211032850

54.

Al-Hakeim

, Al-Rubaye

, Almulla

, et al. Chronic fatigue, depression and anxiety symptoms in long COVID are strongly predicted by neuroimmune and neuro-oxidative pathways which are caused by the inflammation during acute infection. J Clin Med, 2023; 12(2):511; doi: 10.3390/jcm12020511

55.

Cha

, Baek

. Symptoms and management of long COVID: a scoping review. J Clin Nurs, 2021; doi: 10.1111/jocn.16150

56.

Hayes

, Ingram

, Sculthorpe

. More than 100 persistent symptoms of SARS-CoV-2 (Long COVID): a scoping review. Front Med (Lausanne), 2021; 8:750378; doi: 10.3389/fmed.2021.750378

57.

Healey

, Sheikh

, Daines

, et al. Symptoms and signs of long COVID: a rapid review and meta-analysis. J Glob Health, 2022; 12:05014; doi: 10.7189/jogh.12.05014

58.

Espay

, Aybek

, Carson

, et al. Current concepts in diagnosis and treatment of functional neurological disorders. JAMA Neurol, 2018; 75(9):1132–1141; doi: 10.1001/jamaneurol.2018.1264

59.

O'Sullivan

Long-term sequelae following previous coronavirus epidemics. Clin Med (Lond), 2021; 21(1):e68–e70; doi: 10.7861/clinmed.2020-0204

60.

Malkova

, Shoenfeld

. Autoimmune autonomic nervous system imbalance and conditions: chronic fatigue syndrome, fibromyalgia, silicone breast implants, COVID and post-COVID syndrome, sick building syndrome, post-orthostatic tachycardia syndrome, autoimmune diseases and autoimmune/inflammatory syndrome induced by adjuvants. Autoimmun Rev, 2023; 22(1):103230; doi: 10.1016/j.autrev.2022.103231

61.

Nguyen

, Whiteside

, Bulger

, et al. Post-traumatic stress disorder (PTSD) symptoms and alcohol and drug use comorbidity at 25 US level I trauma centers. Trauma Surg Acute Care Open, 2022; 7(1):e000913; doi: 10.1136/tsaco-2022-000913

62.

Smith

, Johnson

, Stewart

. Chronic neuropathologies of single and repetitive TBI: substrates of dementia?. Nat Rev Neurol, 2013; 9(4):211–221; doi: 10.1038/nrneurol.2013.29

63.

Alonso-Canovas

, Kurtis

, Gomez-Mayordomo

, et al. Functional neurological disorders after COVID-19 and SARS-CoV-2 vaccines: a national multicentre observational study. J Neurol Neurosurg Psychiatry, 2023; 94(9):776–777; doi: 10.1136/jnnp-2022-330885

64.

Jarrott

, Head

, Pringle

, et al. “LONG COVID”—a hypothesis for understanding the biological basis and pharmacological treatment strategy. Pharmacol Res Perspect, 2022; 10(1):e00911; doi: 10.1002/prp2.911

65.

Mantovani

, Morrone

, Patrono

, et al. Long Covid: where we stand and challenges ahead. Cell Death Differ, 2022; 29(10):1891–1900; doi: 10.1038/s41418-022-01052-6

66.

Yong

SJ.

Long COVID or post-COVID-19 syndrome: putative pathophysiology, risk factors, and treatments. Infect Dis (Lond), 2021; 53(10):737–754; doi: 10.1080/23744235.2021.1924397

67.

Bauer

, Laksono

, de Vrij

FMS

, et al. The neuroinvasiveness, neurotropism, and neurovirulence of SARS-CoV-2. Trends Neurosci, 2022; 45(5):358–368; doi: 10.1016/j.tins.2022.02.006

68.

McQuaid

, Brady

, Deane

. SARS-CoV-2: is there neuroinvasion?. Fluids Barriers CNS, 2021; 18(1):32; doi: 10.1186/s12987-021-00267-y

69.

Chen

, Julg

, Mohandas

, et al.; RECOVER Mechanistic Pathways Task Force. Viral persistence, reactivation, and mechanisms of long COVID. Elife, 2023; 12:e86015; doi: 10.7554/eLife.86015

70.

Torices

, Motta

, da Rosa

, et al. SARS-CoV-2 infection of human brain microvascular endothelial cells leads to inflammatory activation through NF-κB non-canonical pathway and mitochondrial remodeling. Res Sq, 2022; doi: 10.21203/rs.3.rs-1762855/v1

71.

Rutkai

, Mayer

, Hellmers

, et al. Neuropathology and virus in brain of SARS-CoV-2 infected non-human primates. Nat Commun, 2022; 13(1):1745; doi: 10.1038/s41467-022-29440-z

72.

Wang

, Berger

, Davis

, et al. COVID-19 rebound after Paxlovid and Molnupiravir during January-June 2022. medRxiv, 2022; doi: 10.1101/2022.06.21.22276724

73.

Viszlayová

, Sojka

, Dobrodenková

, et al. SARS-CoV-2 RNA in the cerebrospinal fluid of a patient with long COVID. Ther Adv Infect Dis, 2021; 8:20499361211048572; doi: 10.1177/20499361211048572

74.

Schweitzer

, Goereci

, Franke

, et al. Cerebrospinal fluid analysis post-COVID-19 is not suggestive of persistent central nervous system infection. Ann Neurol, 2022; 91(1):150–157; doi: 10.1002/ana.26262

75.

, Ilyas

, Weng

. Endothelial dysfunction in COVID-19: an overview of evidence, biomarkers, mechanisms and potential therapies. Acta Pharmacol Sin, 2023; 44(4):695–709; doi: 10.1038/s41401-022-00998-0

76.

Ambrosino

, Calcaterra

, Mosella

, et al. Endothelial dysfunction in COVID-19: a unifying mechanism and a potential therapeutic target. Biomedicines, 2022; 10(4):812; doi: 10.3390/biomedicines10040812

77.

Østergaard

SARS CoV-2 related microvascular damage and symptoms during and after COVID-19: consequences of capillary transit-time changes, tissue hypoxia and inflammation. Physiol Rep, 2021; 9(3):e14726; doi: 10.14814/phy2.14726

78.

Zanini

, Selleri

, Roncati

, et al. Vascular “long COVID”: a new vessel disease?. Angiology, 2024; 75(1):8–14; doi: 10.1177/00033197231153204

79.

Acanfora

, Acanfora

, Ciccone

, et al. The cross-talk between thrombosis and inflammatory storm in acute and long-COVID-19: therapeutic targets and clinical cases. Viruses, 2021; 13(10):1904; doi: 10.3390/v13101904

80.

Turner

, Khan

, Putrino

, et al. Long COVID: pathophysiological factors and abnormalities of coagulation. Trends Endocrinol Metab, 2023; 34(6):321–344; doi: 10.1016/j.tem.2023.03.002

81.

Tan

, Komarasamy

, Rmt Balasubramaniam

. Hyperinflammatory immune response and COVID-19: a double edged sword. Front Immunol, 2021; 12:742941; doi: 10.3389/fimmu.2021.742941

82.

Low

, Low

, Akrami

. A review of cytokine-based pathophysiology of Long COVID symptoms. Front Med (Lausanne), 2023; 10:1011936; doi: 10.3389/fmed.2023.1011936

83.

Opsteen

, Files

, Fram

, et al. The role of immune activation and antigen persistence in acute and long COVID. J Investig Med, 2023; 71(5):545–562; doi: 10.1177/10815589231158041

84.

Koelman

, Reichmann

, Börnhorst

, et al. Determinants of elevated chemerin as a novel biomarker of immunometabolism: data from a large population-based cohort. Endocr Connect, 2021; 10(9):1200–1211; doi: 10.1530/ec-21-0273

85.

Voss

, Hong

, Bader

, et al. A guide to interrogating immunometabolism. Nat Rev Immunol, 2021; 21(10):637–652; doi: 10.1038/s41577-021-00529-8

86.

Rudiansyah

, Jasim

, Mohammad Pour

, et al. Coronavirus disease 2019 (COVID-19) update: from metabolic reprogramming to immunometabolism. J Med Virol, 2022; 94(10):4611–4627; doi: 10.1002/jmv.27929

87.

Wang

, Zeng

, Wang

, et al. Immunometabolism and potential targets in severe COVID-19 peripheral immune responses. Asian J Pharm Sci, 2021; 16(6):665–667; doi: 10.1016/j.ajps.2021.07.001

88.

Maes

, Al-Rubaye

, Almulla

, et al. Lowered quality of life in long COVID is predicted by affective symptoms, chronic fatigue syndrome, inflammation and neuroimmunotoxic pathways. Int J Environ Res Public Health, 2022; 19(16):10362; doi: 10.3390/ijerph191610362

89.

Vollbracht

, Kraft

. Oxidative stress and hyper-inflammation as major drivers of severe COVID-19 and long COVID: implications for the benefit of high-dose intravenous vitamin C. Front Pharmacol, 2022; 13:899198; doi: 10.3389/fphar.2022.899198

90.

Yin

, Peluso

, Thomas

, et al. Long COVID manifests with T cell dysregulation, inflammation, and an uncoordinated adaptive immune response to SARS-CoV-2. bioRxiv, 2023; doi: 10.1101/2023.02.09.527892

91.

Ahamed

, Laurence

. Long COVID endotheliopathy: hypothesized mechanisms and potential therapeutic approaches. J Clin Invest, 2022; 132(15):e161167; doi: 10.1172/jci161167

92.

Sherif

, Gomez

, Connors

, et al. Pathogenic mechanisms of post-acute sequelae of SARS-CoV-2 infection (PASC). Elife, 2023; 12:e86002; doi: 10.7554/eLife.86002

93.

Ahmad

, Feigen

, Vazquez

, et al. Neurological sequelae of COVID-19. J Integr Neurosci, 2022; 21(3):77; doi: 10.31083/j.jin2103077

94.

Acharya

, Alameer

, Calpin

, et al. A comprehensive review of vascular complications in COVID-19. J Thromb Thrombolysis, 2022; 53(3):586–593, doi: 10.1007/s11239-021-02593-2

95.

Siddiqi

, Libby

, Ridker

. COVID-19—a vascular disease. Trends Cardiovasc Med, 2021; 31(1):1–5; doi: 10.1016/j.tcm.2020.10.005

96.

Evans

, Rainger

, Mason

, et al. Endothelial dysfunction in COVID-19: a position paper of the ESC Working Group for Atherosclerosis and Vascular Biology, and the ESC Council of Basic Cardiovascular Science. Cardiovasc Res, 2020; 116(14):2177–2184; doi: 10.1093/cvr/cvaa230

97.

Logroscino

, Beghi

. Stroke epidemiology and COVID-19 pandemic. Curr Opin Neurol, 2021; 34(1):3–10; doi: 10.1097/wco.0000000000000879

98.

Siepmann

, Sedghi

, Simon

, et al. Increased risk of acute stroke among patients with severe COVID-19: a multicenter study and meta-analysis. Eur J Neurol, 2021; 28(1):238–247; doi: 10.1111/ene.14535

99.

Shahjouei

, Naderi

, Li

, et al. Risk of stroke in hospitalized SARS-CoV-2 infected patients: a multinational study. EBioMedicine, 2020; 59:102939; doi: 10.1016/j.ebiom.2020.102939

100.

Fridman

, Bullrich

, Jimenez-Ruiz

, et al. Stroke risk, phenotypes, and death in COVID-19: systematic review and newly reported cases. Neurology, 2020; 95(24):e3373–e3385; doi: 10.1212/wnl.0000000000010851

101.

Hadid

, Kafri

, Al-Katib

. Coagulation and anticoagulation in COVID-19. Blood Rev, 2021; 47:100761; doi: 10.1016/j.blre.2020.100761

102.

Astin

, Banerjee

, Baker

, et al. Long COVID: mechanisms, risk factors and recovery. Exp Physiol, 2023; 108(1):12–27; doi: 10.1113/ep090802

103.

Pretorius

, Vlok

, Venter

, et al. Persistent clotting protein pathology in Long COVID/Post-Acute Sequelae of COVID-19 (PASC) is accompanied by increased levels of antiplasmin. Cardiovasc Diabetol, 2021; 20(1):172; doi: 10.1186/s12933-021-01359-7

104.

Kell

, Laubscher

, Pretorius

. A central role for amyloid fibrin microclots in long COVID/PASC: origins and therapeutic implications. Biochem J, 2022; 479(4):537–559; doi: 10.1042/bcj20220016

105.

Castanares-Zapatero

, Chalon

, Kohn

, et al. Pathophysiology and mechanism of long COVID: a comprehensive review. Ann Med, 2022; 54(1):1473–1487; doi: 10.1080/07853890.2022.2076901

106.

Peluso

, Deitchman

, Torres

, et al. Long-term SARS-CoV-2-specific immune and inflammatory responses in individuals recovering from COVID-19 with and without post-acute symptoms. Cell Rep, 2021; 36(6):109518; doi: 10.1016/j.celrep.2021.109518

107.

Shimohata

Neuro-COVID-19. Clin Exp Neuroimmunol, 2021; doi: 10.1111/cen3.12676

108.

Jentho

, Weis

. DAMPs and Innate Immune Training. Front Immunol, 2021; 12:699563; doi: 10.3389/fimmu.2021.699563

109.

Klimova

, Bozhkov

, Lavinska

, et al. Low molecular weight cytotoxic components (DAMPs) form the post-COVID-19 syndrome. Immunobiology, 2023; 228(1):152316; doi: 10.1016/j.imbio.2022.152316

110.

Islam

, Wang

, Abdel-Mohsen

, et al. Tissue injury and leukocyte changes in post-acute sequelae of SARS-CoV-2: review of 2833 post-acute patient outcomes per immune dysregulation and microbial translocation in long COVID. J Leukoc Biol, 2023; 113(3):236–254; doi: 10.1093/jleuko/qiac001

111.

Liang

, Gałecki

, Su

. Unresolved Systemic Inflammation, Long COVID, and the Common Pathomechanisms of Somatic and Psychiatric Comorbidity. J Clin Med, 2022; 11(17):5114; doi: 10.3390/jcm11175114

112.

Stefano

, Büttiker

, Weissenberger

, et al. Editorial: the pathogenesis of long-term neuropsychiatric COVID-19 and the role of microglia, mitochondria, and persistent neuroinflammation: a hypothesis. Med Sci Monit, 2021; 27:e933015; doi: 10.12659/msm.933015

113.

Petersen

Brain imaging and neuropsychological assessment of individuals recovered from a mild to moderate SARS- CoV-2 infection. medRxiv, 2022; doi: <h/> 10.1101/2022.07.08.22277420

114.

Petersen

, Kristiansen

, Hanusson

, et al. Prevalence of long COVID in a national cohort: longitudinal measures from disease onset until 8 months' follow-up. Int J Infect Dis, 2022; 122:437–441; doi: 10.1016/j.ijid.2022.06.031

115.

El-Rhermoul

, Fedorowski

, Eardley

, et al. Autoimmunity in Long Covid and POTS. Oxf Open Immunol, 2023; 4(1):iqad002; doi: 10.1093/oxfimm/iqad002

116.

Sin

DD.

Is long COVID an autoimmune disease?. Eur Respir J, 2023; 61(1):2202272; doi: 10.1183/13993003.02272-2022

117.

Anaya

, Herrán

, Beltrán

, et al. Is post-COVID syndrome an autoimmune disease?. Expert Rev Clin Immunol, 2022; 18(7):653–666; doi: 10.1080/1744666x.2022.2085561

118.

Votto

, Castagnoli

, Marseglia

, et al. COVID-19 and autoimmune diseases: is there a connection?. Curr Opin Allergy Clin Immunol, 2023; 23(2):185–192; doi: 10.1097/aci.0000000000000888

119.

Franke

, Boesl

, Goereci

, et al. Association of cerebrospinal fluid brain-binding autoantibodies with cognitive impairment in post-COVID-19 syndrome. Brain Behav Immun, 2023; 109:139–143; doi: 10.1016/j.bbi.2023.01.006

120.

Needham

Brain Injury in COVID-19 is Associated with Autoinflammation and Autoimmunity. medRxiv, 2021; doi: https://doi.org/10.1101/2021.12.03.21266112

121.

Needham

, Chou

, Coles

, et al. Neurological implications of COVID-19 infections. Neurocrit Care, 2020; 32(3):667–671; doi: 10.1007/s12028-020-00978-4

122.

Needham

, Ren

, Digby

, et al. Brain injury in COVID-19 is associated with dysregulated innate and adaptive immune responses. Brain, 2022; 145(11):4097–4107; doi: 10.1093/brain/awac321

123.

Lindqvist

, Cunningham

, Mulder

, et al. Myoclonus in patients with COVID-19: Findings of autoantibodies against brain structures in cerebrospinal fluid. Eur J Neurol, 2023; doi: 10.1111/ene.15958

124.

Kwak

, Lee

, Woo

, et al. Synergistic cycles of protease activity and inflammation via PPARγ degradation in chronic obstructive pulmonary disease. Exp Mol Med, 2021; 53(5):947–955; doi: 10.1038/s12276-021-00626-7

125.

Zhao

, Zhao

, Zhong

, et al. Targeted protein degradation: mechanisms, strategies and application. Signal Transduct Target Ther, 2022; 7(1):113; doi: 10.1038/s41392-022-00966-4

126.

Venkataramani

, Winkler

. Cognitive deficits in Long Covid-19. N Engl J Med, 2022; 387(19):1813–1815; doi: 10.1056/NEJMcibr2210069

127.

Agoston

, Elsayed

. Serum-based protein biomarkers in blast-induced traumatic brain injury spectrum disorder. Front Neurol, 2012; 3:107; doi: 10.3389/fneur.2012.00107

128.

Bremner

, Wittbrodt

. Stress, the brain, and trauma spectrum disorders. Int Rev Neurobiol, 2020; 152:1–22; doi: 10.1016/bs.irn.2020.01.004

129.

Decuypere

, Klimo

Jr . Spectrum of traumatic brain injury from mild to severe. Surg Clin North Am, 2012; 92(4):939–957, ix; doi: 10.1016/j.suc.2012.04.005

130.

Jordan

BD.

The clinical spectrum of sport-related traumatic brain injury. Nat Rev Neurol, 2013; 9(4):222–230; doi: 10.1038/nrneurol.2013.33

131.

Mayer

, Quinn

, Master

. The spectrum of mild traumatic brain injury: A review. Neurology, 2017; 89(6):623–632; doi: 10.1212/wnl.0000000000004214

132.

Pugh

, Kennedy

, Prager

, et al. Phenotyping the spectrum of traumatic brain injury: a review and pathway to standardization. J Neurotrauma, 2021; 38(23):3222–3234; doi: 10.1089/neu.2021.0059

133.

, Dumkrieger

, Wu

, et al. Sub-classifying patients with mild traumatic brain injury: a clustering approach based on baseline clinical characteristics and 90-day and 180-day outcomes. PLoS One, 2018; 13(7):e0198741; doi: 10.1371/journal.pone.0198741

134.

Teasdale

, Jennett

. Assessment of coma and impaired consciousness. A practical scale. Lancet, 1974; 2(7872):81–84; doi: 10.1016/s0140-6736(74)91639-0

135.

Dikmen

, Machamer

, Manley

, et al.; TRACK-TBI Investigators. Functional Status Examination versus Glasgow Outcome Scale Extended as outcome measures in traumatic brain injuries: how do they compare?. J Neurotrauma, 2019; 36(16):2423–2429; doi: 10.1089/neu.2018.6198

136.

Reith

, Synnot

, van den Brande

, et al. Factors influencing the reliability of the Glasgow Coma Scale: a systematic review. Neurosurgery, 2017; 80(6):829–839; doi: 10.1093/neuros/nyw178

137.

Reith

, Van den Brande

, Synnot

, et al. The reliability of the Glasgow Coma Scale: a systematic review. Intensive Care Med, 2016; 42(1):3–15; doi: 10.1007/s00134-015-4124-3

138.

Segatore

, Way

. The Glasgow Coma Scale: time for change. Heart Lung, 1992; 21(6):548–557.

139.

Giza

, Greco

, Prins

. Concussion: pathophysiology and clinical translation. Handb Clin Neurol, 2018; 158:51–61; doi: 10.1016/b978-0-444-63954-7.00006-9

140.

Echemendia

, Meeuwisse

, McCrory

, et al. The Sport Concussion Assessment Tool 5th Edition (SCAT5): background and rationale. Br J Sports Med, 2017; 51(11):848–850; doi: 10.1136/bjsports-2017-097506

141.

Nasrallah

, Bellapart

, Walsham

, et al. PREdiction and Diagnosis using Imaging and Clinical biomarkers Trial in Traumatic Brain Injury (PREDICT-TBI) study protocol: an observational, prospective, multicentre cohort study for the prediction of outcome in moderate-to-severe TBI. BMJ Open, 2023; 13(4):e067740; doi: 10.1136/bmjopen-2022-067740

142.

Takahashi

, Virmani

, Chung

, et al. Blunt and penetrating severe traumatic brain injury. Neurol Clin, 2021; 39(2):443–469; doi: 10.1016/j.ncl.2021.02.009

143.

Dijkland

, Foks

, Polinder

, et al. Prognosis in moderate and severe traumatic brain injury: a systematic review of contemporary models and validation studies. J Neurotrauma, 2020; 37(1):1–13; doi: 10.1089/neu.2019.6401

144.

Abdelmalik

, Draghic

, Ling

GSF

. Management of moderate and severe traumatic brain injury. Transfusion, 2019; 59(S2):1529–1538; doi: 10.1111/trf.15171

145.

Stocchetti

, Carbonara

, Citerio

, et al. Severe traumatic brain injury: targeted management in the intensive care unit. Lancet Neurol, 2017; 16(6):452–464; doi: 10.1016/s1474-4422(17)30118-7

146.

Golding

EM.

Sequelae following traumatic brain injury. The cerebrovascular perspective. Brain Res Brain Res Rev, 2002; 38(3):377–388.

147.

Papa

, Brophy

, Welch

, et al. Time course and diagnostic accuracy of glial and neuronal blood biomarkers GFAP and UCH-L1 in a large cohort of trauma patients with and without mild traumatic brain injury. JAMA Neurol, 2016; 73(5):551–560; doi: 10.1001/jamaneurol.2016.0039

148.

Rostami

, Gyorgy

, Davidsson

, et al. Time-dependent changes in serum level of protein biomarkers after focal traumatic brain injury. Int J Neurorehabilitation, 2015; 2(3):2–6.

149.

Agoston

, Vink

, Helmy

, et al. How to translate time; the temporal aspects of rodent and human pathobiological processes in traumatic brain injury. J Neurotrauma, 2019; 36(11):1724–1737; doi: 10.1089/neu.2018.6261

150.

Ahmed

, Gyorgy

, Kamnaksh

, et al. Time-dependent changes of protein biomarker levels in the cerebrospinal fluid after blast traumatic brain injury. Electrophoresis, 2012; 33(24):3705–3711; doi: 10.1002/elps.201200299

151.

Gyorgy

, Ling

, Wingo

, et al. Time-dependent changes in serum biomarker levels after blast traumatic brain injury. J Neurotrauma, 2011; 28(6):1121–1126; doi: 10.1089/neu.2010.1561

152.

Lin

, Kamnaksh

, Aniceto

, et al. Time-dependent changes in the biofluid levels of neural injury markers in severe traumatic brain injury patients—cerebrospinal fluid and cerebral microdialysates: a longitudinal prospective pilot study. Neurotrauma Rep, 2023; 4(1):107–117; doi: 10.1089/neur.2022.0076

153.

Thelin

, Zeiler

, Ercole

, et al. Serial sampling of serum protein biomarkers for monitoring human traumatic brain injury dynamics: a systematic review. Front Neurol, 2017; 8:300; doi: 10.3389/fneur.2017.00300

154.

Mohamadpour

, Whitney

, Bergold

. The importance of therapeutic time window in the treatment of traumatic brain injury. Front Neurosci, 2019; 13:07; doi: 10.3389/fnins.2019.00007

155.

Kamins

, Bigler

, Covassin

, et al. What is the physiological time to recovery after concussion? A systematic review. Br J Sports Med, 2017; 51(12):935–940; doi: 10.1136/bjsports-2016-097464

156.

Balança

, Desmurs

, Grelier

, et al. DAMPs and RAGE pathophysiology at the acute phase of brain injury: an overview. Int J Mol Sci, 2021; 22(5):2439; doi: 10.3390/ijms22052439

157.

Liesz

, Dalpke

, Mracsko

, et al. DAMP signaling is a key pathway inducing immune modulation after brain injury. J Neurosci, 2015; 35(2):583–598; doi: 10.1523/jneurosci.2439-14.2015

158.

Thundyil

, Lim

. DAMPs and neurodegeneration. Ageing Res Rev, 2015; 24(Pt A):17–28; doi: 10.1016/j.arr.2014.11.003

159.

Tsitsopoulos

, Abu Hamdeh

, Marklund

. Current opportunities for clinical monitoring of axonal pathology in traumatic brain injury. Front Neurol, 2017; 8:599; doi: 10.3389/fneur.2017.00599

160.

Smith

, Nonaka

, Miller

, et al. Immediate coma following inertial brain injury dependent on axonal damage in the brainstem. J Neurosurg, 2000; 93(2):315–322; doi: 10.3171/jns.2000.93.2.0315

161.

Johnson

, Stewart

, Smith

. Axonal pathology in traumatic brain injury. Exp Neurol, 2013; 246:35–43; doi: 10.1016/j.expneurol.2012.01.013

162.

Povlishock

, Erb

, Astruc

. Axonal response to traumatic brain injury: reactive axonal change, deafferentation, and neuroplasticity. J Neurotrauma, 1992; 9(Suppl 1):S189–S200.

163.

Haber

, Amyot

, Lynch

, et al. Imaging biomarkers of vascular and axonal injury are spatially distinct in chronic traumatic brain injury. J Cereb Blood Flow Metab, 2021; doi: 10.1177/0271678x20985156

164.

Kenney

, Amyot

, Haber

, et al. Cerebral vascular injury in traumatic brain injury. Exp Neurol, 2016; 275 Pt 3:353–366; doi: 10.1016/j.expneurol.2015.05.019

165.

Lynch

, Eisenbaum

, Algamal

, et al. Impairment of cerebrovascular reactivity in response to hypercapnic challenge in a mouse model of repetitive mild traumatic brain injury. J Cereb Blood Flow Metab, 2020; doi: 10.1177/0271678x20954015

166.

Sandsmark

, Bashir

, Wellington

, et al. Cerebral microvascular injury: a potentially treatable endophenotype of traumatic brain injury-induced neurodegeneration. Neuron, 2019; 103(3):367–379; doi: 10.1016/j.neuron.2019.06.002

167.

Schneider

ALC

, Barber

, Temkin

, et al. Associations of preexisting vascular risk factors with outcomes after traumatic brain injury: a TRACK-TBI study. J Head Trauma Rehabil, 2023; 38(2):e88–e98; doi: 10.1097/htr.0000000000000798

168.

Baker

, Agoston

, Brady

, et al. Targeting the cerebrovascular system: next-generation biomarkers and treatment for mild traumatic brain injury. Neuroscientist, 2021; doi: 10.1177/10738584211012264

169.

Werhane

, Evangelista

, Clark

, et al. Pathological vascular and inflammatory biomarkers of acute- and chronic-phase traumatic brain injury. Concussion, 2017; 2(1):Cnc30; doi: 10.2217/cnc-2016-0022

170.

Amyot

, Kenney

, Moore

, et al. Imaging of cerebrovascular function in chronic traumatic brain injury. J Neurotrauma, 2018; 35(10):1116–1123; doi: 10.1089/neu.2017.5114

171.

Sun

, Symons

, O'Brien

, et al. Serum protein biomarkers of inflammation, oxidative stress, and cerebrovascular and glial injury in concussed Australian football players. J Neurotrauma, 2022; 39(11–12):800–808; doi: 10.1089/neu.2021.0493

172.

Major

, McDonald

, O'Brien

, et al. Serum protein biomarker findings reflective of oxidative stress and vascular abnormalities in male, but not female, collision sport athletes. Front Neurol, 2020; 11:549624; doi: 10.3389/fneur.2020.549624

173.

Wright

, Brady

, Kamnaksh

, et al. Repeated mild traumatic brain injuries induce persistent changes in plasma protein and magnetic resonance imaging biomarkers in the rat. Sci Rep, 2019; 9(1):14626; doi: 10.1038/s41598-019-51267-w

174.

Thomas

, Gatson

, Silverman

, et al. von Willebrand factor as a biomarker of traumatic brain injury. Neurology, 2021; 96(15 Supplement):4717.

175.

Sandsmark

, Bogoslovsky

, Qu

, et al. Changes in plasma von Willebrand factor and cellular fibronectin in MRI-defined traumatic microvascular injury. Front Neurol, 2019; 10:246; doi: 10.3389/fneur.2019.00246

176.

Kempuraj

, Ahmed

, Selvakumar

, et al. Mast cell activation, neuroinflammation, and tight junction protein derangement in acute traumatic brain injury. Mediators Inflamm, 2020; 2020:4243953; doi: 10.1155/2020/4243953

177.

Bhowmick

, D'Mello

, Caruso

, et al. Impairment of pericyte-endothelium crosstalk leads to blood-brain barrier dysfunction following traumatic brain injury. Exp Neurol, 2019; 317:260–270; doi: 10.1016/j.expneurol.2019.03.014

178.

Hubbard

, Dong

, Cruz

, et al. Links between thrombosis and inflammation in traumatic brain injury. Thromb Res, 2021; 198:62–71; doi: 10.1016/j.thromres.2020.10.041

179.

Kempuraj

, Ahmed

, Selvakumar

, et al. Acute traumatic brain injury-induced neuroinflammatory response and neurovascular disorders in the brain. Neurotox Res, 2021; 39(2):359–368; doi: 10.1007/s12640-020-00288-9

180.

Sulhan

, Lyon

, Shapiro

, et al. Neuroinflammation and blood-brain barrier disruption following traumatic brain injury: pathophysiology and potential therapeutic targets. J Neurosci Res, 2020; 98(1):19–28; doi: 10.1002/jnr.24331

181.

Frederick

, Louveau

. Meningeal lymphatics, immunity and neuroinflammation. Curr Opin Neurobiol, 2020; 62:41–47; doi: 10.1016/j.conb.2019.11.010

182.

Thelin

, Tajsic

, Zeiler

, et al. Monitoring the neuroinflammatory response following acute brain injury. Front Neurol, 2017; 8:351; doi: 10.3389/fneur.2017.00351

183.

Needham

, Helmy

, Zanier

, et al. The immunological response to traumatic brain injury. J Neuroimmunol, 2019; 332:112–125; doi: 10.1016/j.jneuroim.2019.04.005

184.

Medzhitov

Origin and physiological roles of inflammation. Nature, 2008; 454(7203):428–435; doi: 10.1038/nature07201

185.

McGinn

, Povlishock

. Pathophysiology of traumatic brain injury. Neurosurg Clin N Am, 2016; 27(4):397–407; doi: 10.1016/j.nec.2016.06.002

186.

Marklund

, Vedung

, Lubberink

, et al. Tau aggregation and increased neuroinflammation in athletes after sports-related concussions and in traumatic brain injury patients—a PET/MR study. Neuroimage Clin, 2021; 30:102665; doi: 10.1016/j.nicl.2021.102665

187.

Nitta

, Savitz

, Nelson

, et al. Acute elevation of serum inflammatory markers predicts symptom recovery after concussion. Neurology, 2019; 93(5):e497–e507; doi: 10.1212/wnl.0000000000007864

188.

Perry

, Teeling

. Microglia and macrophages of the central nervous system: the contribution of microglia priming and systemic inflammation to chronic neurodegeneration. Semin Immunopathol, 2013; 35(5):601–612; doi: 10.1007/s00281-013-0382-8

189.

Linnerbauer

, Wheeler

, Quintana

. Astrocyte crosstalk in CNS inflammation. Neuron, 2020; 108(4):608–622; doi: 10.1016/j.neuron.2020.08.012

190.

Bhusal

, Afridi

, Lee

, et al. Bidirectional communication between microglia and astrocytes in neuroinflammation. Curr Neuropharmacol, 2023; 21(10):2020–2029; doi: 10.2174/1570159x21666221129121715

191.

Patani

, Hardingham

, Liddelow

. Functional roles of reactive astrocytes in neuroinflammation and neurodegeneration. Nat Rev Neurol, 2023; 19(7):395–409; doi: 10.1038/s41582-023-00822-1

192.

Wang

, Yang

, Yue

, et al. Plasma anti-glial fibrillary acidic protein autoantibody levels during the acute and chronic phases of traumatic brain injury: a Transforming Research and Clinical Knowledge in Traumatic Brain Injury Pilot Study. J Neurotrauma, 2016; 33(13):1270–1277; doi: 10.1089/neu.2015.3881

193.

Needham

, Stoevesandt

, Thelin

, et al. Complex autoantibody responses occur following moderate to severe traumatic brain injury. J Immunol, 2021; 207(1):90–100; doi: 10.4049/jimmunol.2001309

194.

Tisminetzky

, Delude

, Hebert

, et al. Age, multiple chronic conditions, and COVID-19: a literature review. J Gerontol A Biol Sci Med Sci, 2022; 77(4):872–878; doi: 10.1093/gerona/glaa320

195.

Polidori

, Sies

, Ferrucci

, et al. COVID-19 mortality as a fingerprint of biological age. Ageing Res Rev, 2021; 67:101308; doi: 10.1016/j.arr.2021.101308

196.

Notarte

, de Oliveira

MHS

, Peligro

, et al. Age, sex and previous comorbidities as risk factors not associated with SARS-CoV-2 infection for long COVID-19: a systematic review and meta-analysis. J Clin Med, 2022; 11(24):7314; doi: 10.3390/jcm11247314

197.

Stephenson

, Shafran

, Ladhani

. Long COVID in children and adolescents. Curr Opin Infect Dis, 2022; 35(5):461–467; doi: 10.1097/qco.0000000000000854

198.

Brugler Yonts

Pediatric Long-COVID: a review of the definition, epidemiology, presentation, and pathophysiology. Pediatr Ann, 2022; 51(11):e416–e420; doi: 10.3928/19382359-20220913-06

199.

Peters

, Hsu

, Rao

, et al. Influence of study population definition on the effect of age on outcomes after blunt head trauma. Brain Inj, 2018; 32(13–14):1725–1730; doi: 10.1080/02699052.2018.1520301

200.

Mayer

, Meier

, Dodd

, et al. Prospective study of gray matter atrophy following pediatric mild traumatic brain injury. Neurology, 2023; 100(5):e516–e527; doi: 10.1212/wnl.0000000000201470

201.

Keenan

, Hooper

, Wetherington

, et al. Neurodevelopmental consequences of early traumatic brain injury in 3-year-old children. Pediatrics, 2007; 119(3):e616–e623; doi: 10.1542/peds.2006-2313

202.

Koerte

, Wiegand

TLT

, Bonke

, et al. Diffusion imaging of sport-related repetitive head impacts—a systematic review. Neuropsychol Rev, 2023; 33(1):122–143; doi: 10.1007/s11065-022-09566-z

203.

Badea

, Kamnaksh

, Anderson

, et al. Repeated mild blast exposure in young adult rats results in dynamic and persistent microstructural changes in the brain. Neuroimage Clin, 2018; 18:60–73; doi: 10.1016/j.nicl.2018.01.007

204.

Fletcher-Sandersjoo

, Lindblad

, Thelin

, et al. Serial S100B sampling detects intracranial lesion development in patients on extracorporeal membrane oxygenation. Front Neurol, 2019; 10:512; doi: 10.3389/fneur.2019.00512

205.

Tsilingiris

, Vallianou

, Karampela

, et al. Laboratory findings and biomarkers in Long COVID: what do we know so far? Insights into epidemiology, pathogenesis, therapeutic perspectives and challenges. Int J Mol Sci, 2023; 24(13):10458; doi: 10.3390/ijms241310458

206.

Sun

, Shan

, Yang

, et al. The role of neuroinflammation in post-traumatic epilepsy. Front Neurol, 2021; 12:646152; doi: 10.3389/fneur.2021.646152

207.

Folweiler

, Sandsmark

, Diaz-Arrastia

, et al. Unsupervised machine learning reveals novel traumatic brain injury patient phenotypes with distinct acute injury profiles and long-term outcomes. J Neurotrauma, 2020; 37(12):1431–1444; doi: 10.1089/neu.2019.6705

208.

Sayed

, Culver

, Dams-O'Connor

, et al. Clinical phenotype of dementia after traumatic brain injury. J Neurotrauma, 2013; 30(13):1117–1122; doi: 10.1089/neu.2012.2638

209.

Diaz-Arrastia

, Agostini

, Madden

, et al. Posttraumatic epilepsy: the endophenotypes of a human model of epileptogenesis. Epilepsia, 2009; 50(Suppl 2):14–20; doi: 10.1111/j.1528-1167.2008.02006.x

210.

Agoston

, Shutes-David

, Peskind

. Biofluid biomarkers of traumatic brain injury. Brain Inj, 2017; 31(9):1195–1203; doi: 10.1080/02699052.2017.1357836

211.

Wang

, Yang

, Zhu

, et al. An update on diagnostic and prognostic biomarkers for traumatic brain injury. Expert Rev Mol Diagn, 2018; 18(2):165–180; doi: 10.1080/14737159.2018.1428089

212.

Mondello

, Sorinola

, Czeiter

, et al. Blood-based protein biomarkers for the management of traumatic brain injuries in adults presenting to emergency departments with mild brain injury: a living systematic review and meta-analysis. J Neurotrauma, 2021; 38(8):1086–1106; doi: 10.1089/neu.2017.5182

213.

Yue

, Kobeissy

, Jain

, et al. Neuroinflammatory biomarkers for traumatic brain injury diagnosis and prognosis: a TRACK-TBI Pilot Study. Neurotrauma Rep, 2023; 4(1):171–183; doi: 10.1089/neur.2022.0060

214.

Gardner

, Puccio

, Korley

, et al. Effects of age and time since injury on traumatic brain injury blood biomarkers: a TRACK-TBI study. Brain Commun, 2023; 5(1):fcac316; doi: 10.1093/braincomms/fcac316

215.

Tenovuo

, Diaz-Arrastia

, Goldstein

, et al. Assessing the severity of traumatic brain injury—time for a change?. J Clin Med, 2021; 10(1):148; doi: 10.3390/jcm10010148

216.

Joly

, Darmon

, Dekimpe

, et al. Imbalance of von Willebrand factor and ADAMTS13 axis is rather a biomarker of strong inflammation and endothelial damage than a cause of thrombotic process in critically ill COVID-19 patients. J Thromb Haemost, 2021; 19(9):2193–2198; doi: 10.1111/jth.15445

217.

Yatsiv

, Morganti-Kossmann

, Perez

, et al. Elevated intracranial IL-18 in humans and mice after traumatic brain injury and evidence of neuroprotective effects of IL-18-binding protein after experimental closed head injury. J Cereb Blood Flow Metab, 2002; 22(8):971–978.

218.

Byrne

, Bouchier-Hayes

, Harmey

. Angiogenic and cell survival functions of vascular endothelial growth factor (VEGF). J Cell Mol Med, 2005; 9(4):777–794; doi: 10.1111/j.1582-4934.2005.tb00379.x

219.

Kliche

, Waltenberger

. VEGF receptor signaling and endothelial function. IUBMB Life, 2001; 52(1–2):61–66; doi: 10.1080/15216540252774784

220.

, Yue

, Korley

, et al. High-sensitivity C-reactive protein is a prognostic biomarker of six-month disability after traumatic brain injury: results from the TRACK-TBI Study. J Neurotrauma, 2021; 38(7):918–927; doi: 10.1089/neu.2020.7177

221.

Fischer

, Beck-Sickinger

. Chemerin—exploring a versatile adipokine. Biol Chem, 2022; 403(7):625–642; doi: 10.1515/hsz-2021-0409

222.

Wong

, Perlman

. Immune dysregulation and immunopathology induced by SARS-CoV-2 and related coronaviruses—are we our own worst enemy?. Nat Rev Immunol, 2022; 22(1):47–56; doi: 10.1038/s41577-021-00656-2

223.

Schultheiß

, Willscher

, Paschold

, et al. The IL-1β, IL-6, and TNF cytokine triad is associated with post-acute sequelae of COVID-19. Cell Rep Med, 2022; 3(6):100663; doi: 10.1016/j.xcrm.2022.100663

224.

Liu

, Salinas

. Machine learning for predicting outcomes in trauma. Shock, 2017; 48(5):504–510; doi: 10.1097/shk.0000000000000898

225.

Khalili

, Rismani

, Nematollahi

, et al. Prognosis prediction in traumatic brain injury patients using machine learning algorithms. Sci Rep, 2023; 13(1):960; doi: 10.1038/s41598-023-28188-w

226.

Courville

, Kazim

, Vellek

, et al. Machine learning algorithms for predicting outcomes of traumatic brain injury: a systematic review and meta-analysis. Surg Neurol Int, 2023; 14:262; doi: 10.25259/sni_312_2023

227.

Dietz

, Vaitheesh

, Alkin

, et al. Machine learning in clinical diagnosis, prognostication, and management of acute traumatic spinal cord injury (SCI): a systematic review. J Clin Orthop Trauma, 2022; 35:102046; doi: 10.1016/j.jcot.2022.102046

228.

McDonald

, Shultz

, Agoston

. The known unknowns: an overview of the state of blood-based protein biomarkers of mild traumatic brain injury. J Neurotrauma, 2021; 38(19):2652–2666; doi: 10.1089/neu.2021.0011

229.

Finnie

Animal models of traumatic brain injury: a review. Aust Vet J, 2001; 79(9):628–633.

230.

Marklund

, Hillered

. Animal modelling of traumatic brain injury in preclinical drug development: where do we go from here?. Br J Pharmacol, 2011; 164(4):1207–1229; doi: 10.1111/j.1476-5381.2010.01163.x

231.

Agoston

, Kamnaksh

Modeling the Neurobehavioral Consequences of Blast-Induced Traumatic Brain Injury Spectrum Disorder and Identifying Related Biomarkers. In: Brain Neurotrauma: Molecular, Neuropsychological, and Rehabilitation Aspects. ( Kobeissy

FH.

ed.) CRC Press/Taylor & Francis: Boca Raton, FL; 2015.

232.

Kochanek

, Bramlett

, Dixon

, et al. Approach to modeling, therapy evaluation, drug selection, and biomarker assessments for a multicenter pre-clinical drug screening consortium for acute therapies in severe traumatic brain injury: operation brain trauma therapy. J Neurotrauma, 2016; 33(6):513–522; doi: 10.1089/neu.2015.4113

233.

Shultz

, McDonald

, Vonder Haar

, et al. The potential for animal models to provide insight into mild traumatic brain injury: translational challenges and strategies. Neurosci Biobehav Rev, 2017; 76(Pt B):396–414; doi: 10.1016/j.neubiorev.2016.09.014

234.

Brady

, Casillas-Espinosa

, Agoston

, et al. Modelling traumatic brain injury and posttraumatic epilepsy in rodents. Neurobiol Dis, 2019; 123:8–19; doi: 10.1016/j.nbd.2018.08.007

235.

Povlishock

JT.

Pathophysiology of neural injury: therapeutic opportunities and challenges. Clin Neurosurg, 2000; 46:113–126.

236.

Kochanek

, Dixon

, Mondello

, et al. Multi-center pre-clinical consortia to enhance translation of therapies and biomarkers for traumatic brain injury: operation brain trauma therapy and beyond. Front Neurol, 2018; 9:640; doi: 10.3389/fneur.2018.00640

237.

Kochanek

, Bramlett

, Shear

, et al. Synthesis of findings, current investigations, and future directions: operation brain trauma therapy. J Neurotrauma, 2016; 33(6):606–614; doi: 10.1089/neu.2015.4133

238.

Jullienne

, Salehi

, Affeldt

, et al. Male and female mice exhibit divergent responses of the cortical vasculature to traumatic brain injury. J Neurotrauma, 2018; 35(14):1646–1658; doi: 10.1089/neu.2017.5547

239.

Valera

, Joseph

, Snedaker

, et al. Understanding traumatic brain injury in females: a state-of-the-art summary and future directions. J Head Trauma Rehabil, 2021; 36(1):e1–e17; doi: 10.1097/htr.0000000000000652

240.

Prins

, Hovda

. Developing experimental models to address traumatic brain injury in children. J Neurotrauma, 2003; 20(2):123–137; doi: 10.1089/08977150360547053

241.

Hamm

, Jenkins

, Lyeth

, et al. The effect of age on outcome following traumatic brain injury in rats. J Neurosurg, 1991; 75(6):916–921; doi: 10.3171/jns.1991.75.6.0916

242.

Stocchetti

, Paterno

, Citerio

, et al. Traumatic brain injury in an aging population. J Neurotrauma, 2012; 29(6):1119–1125; doi: 10.1089/neu.2011.1995

243.

Roozenbeek

, Maas

, Menon

. Changing patterns in the epidemiology of traumatic brain injury. Nat Rev Neurol, 2013; 9(4):231–236; doi: 10.1038/nrneurol.2013.22

Traumatic Brain Injury in the Long-COVID Era

Abstract

Background and Introduction

Long-COVID/PASC

Candidate Pathomechanism(s) of Long-COVID/PASC

Direct mechanisms

Indirect mechanisms

Endothelial pathologies

Coagulopathies

Inflammation

Autoimmunity

Autoimmunity in long-COVID/PASC

TBI: A Spectrum of Disorders of Different Disease Endophenotypes

Major Pathobiologies Triggered by TBI: The Disease Endophenotypes

Intersection of Long-COVID/PASC and TBI-Induced Pathobiologies

The Role of Biomarkers

The Role of TBI Models

Summary

Footnotes

Acknowledgments

Funding Information

Author Disclosure Statement

Abbreviations Used

References