Poster No:
1624
Submission Type:
Abstract Submission
Authors:
Emily Dennis1, Kimbra Kenney2, Eamonn Kennedy1, Erin Bigler3, Sidney Hinds II2, Hannah Lindsey1, Mary Newsome1, Mary Jo Pugh1, J Kent Werner2, Robert Shih2, Randall Scheibel4, Maya Troyanskaya4, Gerald York5, William Walker6, David Cifu6, David Tate1, Jessica Gill7, Elisabeth Wilde1
Institutions:
1University of Utah, Salt Lake City, UT, 2Uniformed Services University, Bethesda, MD, 3Brigham Young University, Provo, UT, 4Baylor College of Medicine, Houston, TX, 5Alaska Radiology Associates, Anchorage, AK, 6Virginia Commonwealth University, Richmond, VA, 7Johns Hopkins University, Baltimore, MD
First Author:
Co-Author(s):
David Cifu
Virginia Commonwealth University
Richmond, VA
Introduction:
Traumatic brain injury (TBI) can influence brain health over the lifespan and is associated with advanced, and in some cases accelerated, brain aging,1,2 highlighting the need for further research to understand and mitigate its chronic effects. This is especially true for military populations given their increased risk of TBI, and more debilitating sequelae being associated with combat versus non-combat TBI.3 There is considerable heterogeneity in outcome following TBI, thus more sensitive standardized biomarkers of outcome are needed to identify those with increased health risks to allow for targeted interventions. Blood serum biomarkers have shown promise in predicting outcome and are easier to collect than MRI data.4 Neurofilament light chain (NfL) is a promising biomarker of axonal injury, as these neurofilaments are scaffolding proteins exclusively expressed in neurons. Elevated levels of NfL have been found after TBI,5,6 and higher NfL has been associated with longitudinal volume loss in healthy aging.7 Serum NfL may also be predictive of persistent symptoms5 and cognitive function.7 We examined longitudinal associations between NfL and changes in brain volume using tensor-based morphometry (TBM) in a multisite consortium focused on military mild TBI (mTBI). We hypothesized that higher baseline NfL would be associated with longitudinal volume loss, and that this association would be stronger in those with a history of combat-related TBI.
Methods:
Data included are a subset of the larger, multi-site Long-term Impact of Militarily-relevant Brain Injury Consortium/Chronic Effects of Neurotrauma Consortium (LIMBIC-CENC) prospective longitudinal study, for which 2,200 individuals have neuroimaging data. To date, 380 individuals returned for a second MRI, and 255 of those have blood biomarkers available (mean age=29.5 years, SD=4.6, M/F=219/36, mean scan interval=2.5 years, SD=1.6). Using a structured interview, lifetime history of all possible concussive events (PCEs) was assessed.8 Natural language processing (NLP) was used to categorize all 16,000+ PCEs as taking place in (1) civilian, (2) non-deployed but military-related, (3) combat-deployed but non-combat, or (4) combat action contexts. PCEs were determined to be TBI vs. not based on VA/DoD standards.9 Protein biomarker measurement was performed on the Simoa HD-X Analyzer, which allows for multiplex detection at femtomolar concentrations. Analytes are captured on beads and detected with fluorescent detection antibodies in a "digital" fashion in specialized wells. T1-weighted MRI was collected with prospectively harmonized sequences. We created longitudinal Jacobian determinant images using unbiased_pairwise_registration. Voxel-wise linear mixed effects models were run with site as a random effect and age at baseline, gender, BMI, and scan interval as covariates. Results were corrected for multiple comparisons with searchlight False Discovery Rate (FDR).10
Results:
Across the 255 individuals with longitudinal MRI and blood biomarker data, there was no significant association between baseline NfL and volume changes. Within the sub-group who had a history of combat-related mTBI (n=98), elevated baseline NfL was associated with volume loss in bilateral prefrontal white matter regions and the anterior and posterior aspects of the right dorsal cingulum.
Conclusions:
We report that baseline NfL, a marker of neuronal injury, is predictive of longitudinal changes in brain volume in a sample of US Service Members with a history of combat-related mTBI. Age-related changes in NfL, including both overall increases and increases in variability, appear to emerge around age 60, along with a stronger correlation between baseline NfL and volume loss in participants >60 years old. The fact that we are seeing this pattern in our significantly younger cohort (mean age=29.5 years), and only in the combat TBI group, suggests that we may be seeing evidence of advanced or accelerated aging in the combat mTBI group.
Disorders of the Nervous System:
Neurodegenerative/ Late Life (eg. Parkinson’s, Alzheimer’s) 2
Modeling and Analysis Methods:
Other Methods 1
Keywords:
Blood
Trauma
Other - Traumatic brain injury
1|2Indicates the priority used for review
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Please indicate below if your study was a "resting state" or "task-activation” study.
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Healthy subjects only or patients (note that patient studies may also involve healthy subjects):
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Was this research conducted in the United States?
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Structural MRI
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3.0T
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ANTs
Provide references using APA citation style.
1. Dennis EL, Taylor BA, Newsome MR, Troyanskaya M, Abildskov TJ, Betts AM, et al. Advanced brain age in deployment-related traumatic brain injury: A LIMBIC-CENC neuroimaging study. Brain Inj 2022:1–11.
2 Dennis EL, Vervoordt S, Adamson MM, Houshang A, Bigler ED, Caeyenberghs K, et al. Accelerated Aging after Traumatic Brain Injury: An ENIGMA Multi‐Cohort Mega‐Analysis. Annals of Neurology 2024;96:365–77.
3 Vanderploeg RD, Belanger HG, Horner RD, Spehar AM, Powell-Cope G, Luther SL, et al. Health outcomes associated with military deployment: mild traumatic brain injury, blast, trauma, and combat associations in the Florida National Guard. Arch Phys Med Rehabil 2012;93:1887–95.
4 Al-Adli N, Akbik OS, Rail B, Montgomery E, Caldwell C, Barrie U, et al. The clinical use of serum biomarkers in traumatic brain injury: A systematic review stratified by injury severity. World Neurosurg 2021;155:e418–38.
5 Shahim P, Politis A, van der Merwe A, Moore B, Chou Y-Y, Pham DL, et al. Neurofilament light as a biomarker in traumatic brain injury. Neurology 2020;95:e610–22.
6 Bazarian JJ, Korley F, Mannix R. Biomarkers may provide unique insights into neurological effects associated with sport-related concussions. JAMA Netw Open 2020;3:e1919799.
7 Khalil M, Pirpamer L, Hofer E, Voortman MM, Barro C, Leppert D, et al. Serum neurofilament light levels in normal aging and their association with morphologic brain changes. Nat Commun 2020;11.: https://doi.org/10.1038/s41467-020-14612-6.
8 Walker WC, Cifu DX, Hudak AM, Goldberg G, Kunz RD, Sima AP. Structured interview for mild traumatic brain injury after military blast: inter-rater agreement and development of diagnostic algorithm. J Neurotrauma 2015;32:464–73.
9 for Disease Control and Prevention C. DoD/VA code proposal: DOD/VA common definition of TBI. , GA: Centers for Disease Control and … n.d.
10 Langers DR, Jansen JF, Backes WH. Enhanced signal detection in neuroimaging by means of regional control of the global false discovery rate. Neuroimage 2007;38:43–56.
No