Blood biomarkers are associated with brain function and blood flow following sport concussion

Battista, Alex P. Di; Churchill, Nathan W.; Schweizer, Tom A.; Rhind, Shawn G.; Richards, Doug; Baker, Andrew J.; Hutchison, Michael

doi:10.1016/j.jneuroim.2018.03.002

Cited by 34 publications

(29 citation statements)

References 72 publications

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“…Following TBI, peripheral blood levels of diverse cytokines undergo a pronounced increase, which typically peaks hours or days after injury ( 82 , 83 ). Higher acute blood levels of interleukin (IL)-6 ( 134 – 137 ), IL-10 ( 134 , 138 , 139 ), TNF-alpha ( 137 , 140 , 141 ), as well as other cytokines ( 83 ) after TBI have been linked to poor outcomes. Similarly, in chronic TBI, increased blood levels of IL-6 and TNF-α relate to TBI symptoms in military personnel ( 137 , 142 ).…”

Section: Extracellular Vesicles In the Central Nervous System And Neumentioning

confidence: 99%

Extracellular Vesicle Proteins and MicroRNAs as Biomarkers for Traumatic Brain Injury

et al. 2020

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Traumatic brain injury (TBI) is a heterogeneous condition, associated with diverse etiologies, clinical presentations and degrees of severity, and may result in chronic neurobehavioral sequelae. The field of TBI biomarkers is rapidly evolving to address the many facets of TBI pathology and improve its clinical management. Recent years have witnessed a marked increase in the number of publications and interest in the role of extracellular vesicles (EVs), which include exosomes, cell signaling, immune responses, and as biomarkers in a number of pathologies. Exosomes have a well-defined lipid bilayer with surface markers that reflect the cell of origin and an aqueous core that contains a variety of biological material including proteins (e.g., cytokines and growth factors) and nucleic acids (e.g., microRNAs). The presence of proteins associated with neurodegenerative changes such as amyloid-β, α-synuclein and phosphorylated tau in exosomes suggests a role in the initiation and propagation of neurological diseases. However, mechanisms of cell communication involving exosomes in the brain and their role in TBI pathology are poorly understood. Exosomes are promising TBI biomarkers as they can cross the blood-brain barrier and can be isolated from peripheral fluids, including serum, saliva, sweat, and urine. Exosomal content is protected from enzymatic degradation by exosome membranes and reflects the internal environment of their cell of origin, offering insights into tissue-specific pathological processes. Challenges in the clinical use of exosomal cargo as biomarkers include difficulty in isolating pure exosomes, variable yields of the isolation processes, quantification of vesicles, and lack of specificity of exosomal markers. Moreover, there is no consensus regarding nomenclature and characteristics of EV subtypes. In this review, we discuss current technical limitations and challenges of using exosomes and other EVs as blood-based biomarkers, highlighting their potential as diagnostic and prognostic tools in TBI.

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Section: Extracellular Vesicles In the Central Nervous System And Neumentioning

confidence: 99%

Extracellular Vesicle Proteins and MicroRNAs as Biomarkers for Traumatic Brain Injury

et al. 2020

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“…Plasma tau has been shown to be related to some neuroimaging metrics in patients with TBI. Di Battista and colleagues 21 found a stronger correlation between peripheral tau level and cerebral blood flow and global neural connectivity in recently concussed athletes compared with non-concussed athletes and athletes with a history of remote concussion. The authors speculated this may be the result of a compromised glymphatic system resulting in diminished cerebral waste removal.…”

Section: Introductionmentioning

confidence: 98%

Plasma Tau and Amyloid Are Not Reliably Related to Injury Characteristics, Neuropsychological Performance, or White Matter Integrity in Service Members with a History of Traumatic Brain Injury

Yeh

Gill

French

et al. 2019

Journal of Neurotrauma

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The aim of this study was to examine the relationship between plasma tau and amyloid beta-42 (Ab42), neuropsychological functioning, and white matter integrity in U.S. military service members with (n = 155) and without (n = 42) a history of uncomplicated mild (n = 83), complicated mild (n = 26), or moderate, severe, or penetrating (n = 46) traumatic brain injury (TBI). We hypothesized that higher levels of tau and Ab42 would be related to reduced neurocognitive performance and white matter integrity. Participants were enrolled prospectively from Walter Reed National Military Medical Center. Participants completed a blood draw, neuropsychological assessment, and diffusion tensor imaging (General Electric 3T) of the whole brain. From 20 neuropsychological test scores, five cognitive domain scores were computed. Measures of fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) were generated for 18 regions of interest (ROIs). There was no relationship found between the plasma biomarkers and neurocognitive performance in any of the three TBI groups (all ps >0.05; all R 2 changes <0.146). Although not reaching statistical significance after correction for multiple comparisons, higher tau and Ab42 tended to be related to higher FA and lower MD, RD, and AD in patients with a history of moderate, severe, or penetrating TBI. There was no consistent relationship between either of the biomarkers and white matter integrity in the complicated and uncomplicated mild TBI groups. In addition, there was no significant relationship between the biomarkers and age, education, sex, race, bodily injury severity, time since injury, TBI severity, or number of TBIs (all ps >0.15). Future investigation in larger samples of moderate, severe, and penetrating TBI are needed. Other plasma biomarkers, including phosphorylated tau, exosomal tau, and interleukin-10, may be more promising measures to use in the diagnosis, management, and treatment of TBI.

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“…Recently, studies employing advanced neuroimaging and fluid biomarkers have enhanced our knowledge of the mechanistic underpinnings of SRC in humans. These investigations have yielded evidence to support acute and subacute structural and functional alterations in the brain, including changes to functional connectivity [6–8] and cerebral blood flow [7, 9], axonal/neuronal injury [10–13], oxidative damage/stress [14], and inflammation [7, 15, 16]. In a number of cases, perturbations have also been identified at medical clearance [6, 7, 14, 17], suggesting a possible disconnect between clinical and biological recovery.…”

Section: Introductionmentioning

confidence: 99%

Evidence of a distinct peripheral inflammatory profile in sport-related concussion

Battista

Churchill

Rhind

et al. 2019

J Neuroinflammation

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BackgroundInflammation is considered a hallmark of concussion pathophysiology in experimental models, yet is understudied in human injury. Despite the growing use of blood biomarkers in concussion, inflammatory biomarkers have not been well characterized. Furthermore, it is unclear if the systemic inflammatory response to concussion differs from that of musculoskeletal injury. The purpose of this paper was to characterize systemic inflammation after injury in athletes with sport-related concussion or musculoskeletal injury.MethodsA prospective, observational cohort study was conducted employing 175 interuniversity athletes (sport-related concussion, n = 43; musculoskeletal injury, n = 30; healthy, n = 102) from 12 sports at a sports medicine clinic at an academic institution.High-sensitivity immunoassay was used to evaluate 20 inflammatory biomarkers in the peripheral blood of athletes within 7 days of injury (subacute) and at medical clearance. Healthy athletes were sampled prior to the start of their competitive season. Partial least squares regression analyses were used to identify salient biomarker contributions to class separation between injured and healthy athletes, as well as to evaluate the relationship between biomarkers and days to recovery in injured athletes.ResultsIn the subacute period after injury, compared to healthy athletes, athletes with sport-related concussion had higher levels of the chemokines’ monocyte chemoattractant protein-4 (p < 0.001) and macrophage inflammatory protein-1β (p = 0.001); athletes with musculoskeletal injury had higher levels of thymus and activation-regulated chemokine (p = 0.001). No significant differences in biomarker profiles were observed at medical clearance. Furthermore, concentrations of monocyte chemoattractant protein-1 (p = 0.007) and monocyte chemoattractant protein-4 (p < 0.001) at the subacute time point were positively correlated with days to recovery in athletes with sport-related concussion, while thymus and activation-regulated chemokine was (p = 0.001) positively correlated with days to recovery in athletes with musculoskeletal injury.ConclusionSport-related concussion is associated with perturbations to systemic inflammatory chemokines that differ from those observed in athletes with a musculoskeletal injury. These results support inflammation as an important facet of secondary injury after sport-related concussion that can be measured systemically in a human model of injury.Electronic supplementary materialThe online version of this article (10.1186/s12974-019-1402-y) contains supplementary material, which is available to authorized users.

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Blood biomarkers are associated with brain function and blood flow following sport concussion

Cited by 34 publications

References 72 publications

Extracellular Vesicle Proteins and MicroRNAs as Biomarkers for Traumatic Brain Injury

Extracellular Vesicle Proteins and MicroRNAs as Biomarkers for Traumatic Brain Injury

Plasma Tau and Amyloid Are Not Reliably Related to Injury Characteristics, Neuropsychological Performance, or White Matter Integrity in Service Members with a History of Traumatic Brain Injury

Evidence of a distinct peripheral inflammatory profile in sport-related concussion

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