Axonal marker neurofilament light predicts long-term outcomes and progressive neurodegeneration after traumatic brain injury

Graham, Neil; Zimmerman, Karl; Moro, Federico; Heslegrave, Amanda; Maillard, Samia Abed; Bernini, Adriano; Miroz, John‐Paul; Donat, Cornelius K.; Lopez, Maria Yanez; Bourke, Niall; Jolly, Amy; Mallas, Emma-Jane; Soreq, Eyal; Wilson, Mark; Fatania, Gavin; Roi, Dylan; Patel, Maneesh C.; Garbero, Elena; Nattino, Giovanni; Baciu, Camelia; Fainardi, Enrico; Chieregato, Arturo; Gradišek, Primož; Magnoni, Sandra; Oddo, Mauro; Zetterberg, Henrik; Bertolini, Guido; Sharp, David J.

doi:10.1126/scitranslmed.abg9922

Cited by 112 publications

(131 citation statements)

References 73 publications

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“…There are however no studies specifically investigating such patterns and correlation to stroke location. Correlation with lesion volume is seen in other neurological disorders as well; in a recent study of 197 patients with traumatic brain injury, serum measurements of GFAP, NFL, tau and UCHL1 correlated with lesion volume on MRI [ 3 ]. In multiple sclerosis, serum NFL correlates with lesion load, lesion volume and gadolinium enhancing lesions on MRI [ 25 , 26 ].…”

Section: Discussionmentioning

confidence: 99%

“…MBP The concentrations of MBP were 10-1000 times higher than the other investigated proteins, depending on anatomical region. The concentration of MBP was highest in cerebral white matter (16,000 [1][2][3][4][5][6][7][8][9][10][11][12][12][13][14][15][16][17][18][19][20] to 21,000 [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][17][18][19][20][21][22][23][24][25][26][27] µg/g) and approximately tenfold to the one in cerebral cortex (1700 [1100-2600] to 2300 [1700-3100] µg/g). Intermediate levels were seen in the hippocampus, intern...…”

Section: Total Proteinmentioning

confidence: 99%

“…Measurement of such proteins in CSF or blood can be used to detect and assess injury to the nervous system in neurological diseases and trauma, e.g. multiple sclerosis, amyotrophic lateral sclerosis, stroke and traumatic brain injury [1][2][3]. Many neuroglial proteins are unique to one cell type.…”

Section: Introductionmentioning

confidence: 99%

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Distribution of five clinically important neuroglial proteins in the human brain

et al. 2022

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Glial fibrillary acidic protein (GFAP), myelin basic protein (MBP), neurofilament light chain (NFL), tau and ubiquitin carboxy-terminal hydrolase L1 (UCHL1) are five neuroglial proteins that are used as CSF or blood biomarkers of tissue damage in the nervous system. There is incomplete knowledge of how the concentration of these proteins differs between anatomical regions in the CNS as previous studies have focused on gene expression or non-quantitative protein analyses, limiting the interpretability of these biomarkers. The purpose of this study was to create a map of the tissue content of these proteins in different regions of the CNS. The concentrations of the investigated proteins were determined with ELISA in post mortem tissue homogenates from 17 selected anatomical regions in the CNS from ten deceased donors aged 24 to 50 years. When appropriate, the protein concentrations were adjusted for post-mortem interval. In total, 168 tissue samples were analysed. There was a substantial variation in the concentrations of GFAP, MBP, NFL, tau and UCHL1 between different CNS regions. Highly myelinated areas of the CNS had tenfold higher MBP concentration than cerebral cortex, whereas tau showed an inverse pattern. GFAP, NFL and tau displayed an anteroposterior gradient in cerebral white matter. The cerebellum had low concentrations of all the investigated proteins. In conclusion, the tissue concentrations of GFAP, MBP, NFL, tau and UCHL1 were determined throughout the CNS. This information can be used as a reference when interpreting circulating levels of these biomarkers in relation to the extent and localisation of CNS-damaging processes.

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Section: Discussionmentioning

confidence: 99%

Section: Total Proteinmentioning

confidence: 99%

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Distribution of five clinically important neuroglial proteins in the human brain

et al. 2022

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“…Despite the predictive value of the GCS being described some decades ago, at present, there are no biomarkers known to predict patient outcomes in routine clinical use. Several markers have been suggested to be predictive of long-term outcomes in TBI patients, such as inflammatory mediators including IL-1β, IL-10, IL-33, TNF-α and IL-6 [ 32 , 41 , 42 , 44 – 46 ]. Preliminary studies have also suggested a prognostic role for neuron- or glial cell-specific proteins, such as S100B, neurofilament light, neuro-specific enolase, myelin basic protein (MBP), glial fibrillary acidic protein (GFAP), phosphorylated axonal neurofilament subunit H (pNF-H), tau protein and ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1).…”

Section: Discussionmentioning

confidence: 99%

Interleukin-6 as a prognostic biomarker of clinical outcomes after traumatic brain injury: a systematic review

et al. 2022

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Traumatic brain injury (TBI) is a major cause of mortality and morbidity worldwide. There are currently no early biomarkers for prognosis in routine clinical use. Interleukin-6 (IL-6) is a potential biomarker in the context of the established role of neuroinflammation in TBI recovery. Therefore, a systematic review of the literature was performed to assess and summarise the evidence for IL-6 secretion representing a useful biomarker for clinical outcomes. A multi-database literature search between January 1946 and July 2021 was performed. Studies were included if they reported adult TBI patients with IL-6 concentration in serum, cerebrospinal fluid (CSF) and/or brain parenchyma analysed with respect to functional outcome and/or mortality. A synthesis without meta-analysis is reported. Fifteen studies were included, reporting 699 patients. Most patients were male (71.7%), and the pooled mean age was 40.8 years; 78.1% sustained severe TBI. Eleven studies reported IL-6 levels in serum, six in CSF and one in the parenchyma. Five studies on serum demonstrated higher IL-6 concentrations were associated with poorer outcomes, and five showed no signification association. In CSF studies, one found higher IL-6 levels were associated with poorer outcomes, one found them to predict better outcomes and three found no association. Greater parenchymal IL-6 was associated with better outcomes. Despite some inconsistency in findings, it appears that exaggerated IL-6 secretion predicts poor outcomes after TBI. Future efforts require standardisation of IL-6 measurement practices as well as assessment of the importance of IL-6 concentration dynamics with respect to clinical outcomes, ideally within large prospective studies. Prospero registration number: CRD42021271200

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“…The differences in trajectory may be due to sampling times (decrease may not be linear), differences in demographics, AIND subtype, or immunotherapy regimen. It is notable that NfL may remain elevated relative to our neurologic control patients for > 1 year after immunotherapy initiation; this has been noted in patients after a monophasic traumatic brain injury as well (22)(23)(24). Further studies may look at whether this is a chronic state or if the NfL level would decrease further with additional immunotherapy, and if differences in trajectories for a similar AIND would be seen between different immunotherapy regimens.…”

Section: Discussionmentioning

confidence: 75%

Evaluation of Plasma Neurofilament Light Chain Levels as a Biomarker of Neuronal Injury in the Active and Chronic Phases of Autoimmune Neurologic Disorders

et al. 2022

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ObjectiveTo evaluate plasma neurofilament light (NfL) levels in autoimmune neurologic disorders (AINDs) and autoimmune encephalitis (AE).BackgroundEach particular neural autoantibody syndrome has a different clinical phenotype, making one unifying clinical outcome measure difficult to assess. While this is a heterogeneous group of disorders, the final common pathway is likely CNS damage and inflammation. Defining a biomarker of CNS injury that is easily obtainable through a blood sample and reflects a positive treatment response would be highly advantageous in future therapeutic trials. Measurement of blood concentration of neurofilament light (NfL) chain, however, may provide a biomarker of central nervous system (CNS) injury in AE and other AINDs. Here we provide an initial evaluation of plasma NfL levels in AE as well as other AINDs during active and chronic phases of disease and demonstrate its potential utility as a minimally-invasive biomarker for AE and AINDs.Design/MethodsPatients were retrospectively identified who were enrolled in the biorepository at the Rocky Mountain MS Center at the University of Colorado, or were prospectively enrolled after initial presentation. Patients had a well-defined AIND and were followed between 2014 and 2021. NfL was tested using the Single Molecule Array (SIMOA) technology. Patients with headaches but without other significant neurologic disease were included as controls.ResultsTwenty-six plasma and 14 CSF samples of patients with AINDs, and 20 plasma control samples stored in the biorepository were evaluated. A positive correlation was found between plasma and CSF NfL levels for patients with an AIND (R2 = 0.83, p < 0.001). Elevated plasma levels of NfL were seen in patients with active AE compared to controls [geometric mean (GM) 51.4 vs. 6.4 pg/ml, p = 0.002]. Patients with chronic symptoms (>6 months since new or worsening symptoms) of AE or cerebellar ataxia (CA) showed a trend toward lower plasma NfL levels (GM 15.1 pg/ml) compared to active AE or CA. Six patients with longitudinal, prospective sampling available demonstrated a trend in decreased plasma NfL levels over time.ConclusionsOur findings support the use of plasma NfL as a potential minimally-invasive biomarker of CNS injury.

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Axonal marker neurofilament light predicts long-term outcomes and progressive neurodegeneration after traumatic brain injury

Abstract: Axonal injury after TBI can be reliably quantified using plasma NfL, which predicts long-term functional outcomes and progressive neurodegeneration.

Cited by 112 publications

References 73 publications

Distribution of five clinically important neuroglial proteins in the human brain

Distribution of five clinically important neuroglial proteins in the human brain

Interleukin-6 as a prognostic biomarker of clinical outcomes after traumatic brain injury: a systematic review

Evaluation of Plasma Neurofilament Light Chain Levels as a Biomarker of Neuronal Injury in the Active and Chronic Phases of Autoimmune Neurologic Disorders

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