The neuropathological basis of elevated serum neurofilament light following experimental concussion
Abstract Mild traumatic brain injury (mTBI) or concussion is a substantial health problem globally, with up to 15% of patients experiencing persisting symptoms that can significantly impact quality of life. Currently, the diagnosis of mTBI relies on clinical presentation with ancillary neuroimaging...
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BMC
2024-12-01
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| Series: | Acta Neuropathologica Communications |
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| Online Access: | https://doi.org/10.1186/s40478-024-01883-z |
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| author | John D. Arena Douglas H. Smith Ramon Diaz Arrastia D. Kacy Cullen Rui Xiao Jiaxin Fan Danielle C. Harris Cillian E. Lynch Victoria E. Johnson |
| author_facet | John D. Arena Douglas H. Smith Ramon Diaz Arrastia D. Kacy Cullen Rui Xiao Jiaxin Fan Danielle C. Harris Cillian E. Lynch Victoria E. Johnson |
| author_sort | John D. Arena |
| collection | DOAJ |
| description | Abstract Mild traumatic brain injury (mTBI) or concussion is a substantial health problem globally, with up to 15% of patients experiencing persisting symptoms that can significantly impact quality of life. Currently, the diagnosis of mTBI relies on clinical presentation with ancillary neuroimaging to exclude more severe forms of injury. However, identifying patients at risk for a poor outcome or protracted recovery is challenging, in part due to the lack of early objective tests that reflect the relevant underlying pathology. While the pathophysiology of mTBI is poorly understood, axonal damage caused by rotational forces is now recognized as an important consequence of injury. Moreover, serum measurement of the neurofilament light (NfL) protein has emerged as a potentially promising biomarker of injury. Understanding the pathological processes that determine serum NfL dynamics over time, and the ability of NfL to reflect underlying pathology will be critical for future clinical research aimed at reducing the burden of disability after mild TBI. Using a gyrencephalic model of head rotational acceleration scaled to human concussion, we demonstrate significant elevations in serum NfL, with a peak at 3 days post-injury. Moreover, increased serum NfL was detectable out to 2 weeks post-injury, with some evidence it follows a biphasic course. Subsequent quantitative histological examinations demonstrate that axonal pathology, including in the absence of neuronal somatic degeneration, was the likely source of elevated serum NfL. However, the extent of axonal pathology quantified via multiple markers did not correlate strongly with the extent of serum NfL. Interestingly, the extent of blood–brain barrier (BBB) permeability offered more robust correlations with serum NfL measured at multiple time points, suggesting BBB disruption is an important determinant of serum biomarker dynamics after mTBI. These data provide novel insights to the temporal course and pathological basis of serum NfL measurements that inform its utility as a biomarker in mTBI. |
| format | Article |
| id | doaj-art-865cf888570340b89bcbcc8ee4ccade3 |
| institution | OA Journals |
| issn | 2051-5960 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | BMC |
| record_format | Article |
| series | Acta Neuropathologica Communications |
| spelling | doaj-art-865cf888570340b89bcbcc8ee4ccade32025-08-20T02:31:05ZengBMCActa Neuropathologica Communications2051-59602024-12-0112111810.1186/s40478-024-01883-zThe neuropathological basis of elevated serum neurofilament light following experimental concussionJohn D. Arena0Douglas H. Smith1Ramon Diaz Arrastia2D. Kacy Cullen3Rui Xiao4Jiaxin Fan5Danielle C. Harris6Cillian E. Lynch7Victoria E. Johnson8Department of Neurosurgery, Penn Center for Brain Injury and Repair, Perelman School of Medicine, University of PennsylvaniaDepartment of Neurosurgery, Penn Center for Brain Injury and Repair, Perelman School of Medicine, University of PennsylvaniaDepartment of Neurology, Perelman School of Medicine, University of PennsylvaniaDepartment of Neurosurgery, Penn Center for Brain Injury and Repair, Perelman School of Medicine, University of PennsylvaniaThe Department of Biostatistics, Epidemiology and Informatics, University of PennsylvaniaThe Department of Biostatistics, Epidemiology and Informatics, University of PennsylvaniaDepartment of Neurosurgery, Penn Center for Brain Injury and Repair, Perelman School of Medicine, University of PennsylvaniaDepartment of Neurology, Perelman School of Medicine, University of PennsylvaniaDepartment of Neurosurgery, Penn Center for Brain Injury and Repair, Perelman School of Medicine, University of PennsylvaniaAbstract Mild traumatic brain injury (mTBI) or concussion is a substantial health problem globally, with up to 15% of patients experiencing persisting symptoms that can significantly impact quality of life. Currently, the diagnosis of mTBI relies on clinical presentation with ancillary neuroimaging to exclude more severe forms of injury. However, identifying patients at risk for a poor outcome or protracted recovery is challenging, in part due to the lack of early objective tests that reflect the relevant underlying pathology. While the pathophysiology of mTBI is poorly understood, axonal damage caused by rotational forces is now recognized as an important consequence of injury. Moreover, serum measurement of the neurofilament light (NfL) protein has emerged as a potentially promising biomarker of injury. Understanding the pathological processes that determine serum NfL dynamics over time, and the ability of NfL to reflect underlying pathology will be critical for future clinical research aimed at reducing the burden of disability after mild TBI. Using a gyrencephalic model of head rotational acceleration scaled to human concussion, we demonstrate significant elevations in serum NfL, with a peak at 3 days post-injury. Moreover, increased serum NfL was detectable out to 2 weeks post-injury, with some evidence it follows a biphasic course. Subsequent quantitative histological examinations demonstrate that axonal pathology, including in the absence of neuronal somatic degeneration, was the likely source of elevated serum NfL. However, the extent of axonal pathology quantified via multiple markers did not correlate strongly with the extent of serum NfL. Interestingly, the extent of blood–brain barrier (BBB) permeability offered more robust correlations with serum NfL measured at multiple time points, suggesting BBB disruption is an important determinant of serum biomarker dynamics after mTBI. These data provide novel insights to the temporal course and pathological basis of serum NfL measurements that inform its utility as a biomarker in mTBI.https://doi.org/10.1186/s40478-024-01883-zMild traumatic brain injuryConcussionNeurofilament lightBlood brain barrierDiffuse axonal injurySerum biomarkers |
| spellingShingle | John D. Arena Douglas H. Smith Ramon Diaz Arrastia D. Kacy Cullen Rui Xiao Jiaxin Fan Danielle C. Harris Cillian E. Lynch Victoria E. Johnson The neuropathological basis of elevated serum neurofilament light following experimental concussion Acta Neuropathologica Communications Mild traumatic brain injury Concussion Neurofilament light Blood brain barrier Diffuse axonal injury Serum biomarkers |
| title | The neuropathological basis of elevated serum neurofilament light following experimental concussion |
| title_full | The neuropathological basis of elevated serum neurofilament light following experimental concussion |
| title_fullStr | The neuropathological basis of elevated serum neurofilament light following experimental concussion |
| title_full_unstemmed | The neuropathological basis of elevated serum neurofilament light following experimental concussion |
| title_short | The neuropathological basis of elevated serum neurofilament light following experimental concussion |
| title_sort | neuropathological basis of elevated serum neurofilament light following experimental concussion |
| topic | Mild traumatic brain injury Concussion Neurofilament light Blood brain barrier Diffuse axonal injury Serum biomarkers |
| url | https://doi.org/10.1186/s40478-024-01883-z |
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