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Article ; Online: Author Response: Exosomal Neurofilament Light: A Prognostic Biomarker for Remote Symptoms After Mild Traumatic Brain Injury?

Kenney, Kimbra / Guedes, Vivian A / Gill, Jessica M

2021 Volume 96, Issue 15, Page(s) 726

MeSH term(s)	Biomarkers ; Brain Concussion ; Humans ; Intermediate Filaments ; Neurofilament Proteins ; Prognosis
Chemical Substances	Biomarkers ; Neurofilament Proteins
Language	English
Publishing date	2021-04-08
Publishing country	United States
Document type	Journal Article ; Comment
ZDB-ID	207147-2
ISSN	1526-632X ; 0028-3878
ISSN (online)	1526-632X
ISSN	0028-3878
DOI	10.1212/WNL.0000000000011786
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Article ; Online: Long Noncoding RNA VLDLR-AS1 Levels in Serum Correlate with Combat-Related Chronic Mild Traumatic Brain Injury and Depression Symptoms in US Veterans.

Patel, Rekha S / Krause-Hauch, Meredith / Kenney, Kimbra / Miles, Shannon / Nakase-Richardson, Risa / Patel, Niketa A

International journal of molecular sciences

2024 Volume 25, Issue 3

Abstract: More than 75% of traumatic brain injuries (TBIs) are mild (mTBI) and military service members often experience repeated combat-related mTBI. The chronic comorbidities concomitant with repetitive mTBI (rmTBI) include depression, post-traumatic stress ... ...

Abstract	More than 75% of traumatic brain injuries (TBIs) are mild (mTBI) and military service members often experience repeated combat-related mTBI. The chronic comorbidities concomitant with repetitive mTBI (rmTBI) include depression, post-traumatic stress disorder or neurological dysfunction. This study sought to determine a long noncoding RNA (lncRNA) expression signature in serum samples that correlated with rmTBI years after the incidences. Serum samples were obtained from Long-Term Impact of Military-Relevant Brain-Injury Consortium Chronic Effects of Neurotrauma Consortium (LIMBIC CENC) repository, from participants unexposed to TBI or who had rmTBI. Four lncRNAs were identified as consistently present in all samples, as detected via droplet digital PCR and packaged in exosomes enriched for CNS origin. The results, using qPCR, demonstrated that the lncRNA VLDLR-AS1 levels were significantly lower among individuals with rmTBI compared to those with no lifetime TBI. ROC analysis determined an AUC of 0.74 (95% CI: 0.6124 to 0.8741;
MeSH term(s)	Humans ; Veterans/psychology ; Brain Concussion/epidemiology ; Brain Concussion/genetics ; Brain Concussion/complications ; RNA, Long Noncoding/genetics ; Depression/genetics ; Brain Injuries, Traumatic/genetics ; Brain Injuries, Traumatic/complications
Chemical Substances	RNA, Long Noncoding
Language	English
Publishing date	2024-01-25
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms25031473
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Article ; Online: Risk of Dementia Outcomes Associated With Traumatic Brain Injury During Military Service.

Kenney, Kimbra / Diaz-Arrastia, Ramon

JAMA neurology

2018 Volume 75, Issue 9, Page(s) 1043–1044

MeSH term(s)	Brain Concussion ; Brain Injuries, Traumatic ; Dementia ; Humans ; Military Personnel ; Unconsciousness ; Veterans
Language	English
Publishing date	2018-07-02
Publishing country	United States
Document type	Editorial ; Comment
ZDB-ID	2702023-X
ISSN	2168-6157 ; 2168-6149
ISSN (online)	2168-6157
ISSN	2168-6149
DOI	10.1001/jamaneurol.2018.0347
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Article ; Online: White Matter Hyperintensities Are Not Related to Symptomatology or Cognitive Functioning in Service Members with a Remote History of Traumatic Brain Injury.

Lippa, Sara M / Kenney, Kimbra / Riedy, Gerard / Ollinger, John

Neurotrauma reports

2021 Volume 2, Issue 1, Page(s) 245–254

Abstract: This study aimed to determine whether magnetic resonance imaging (MRI) white matter hyperintensities (WMHs) are associated with symptom reporting and/or cognitive performance in 1202 active-duty service members with prior single or multiple mild ... ...

Abstract	This study aimed to determine whether magnetic resonance imaging (MRI) white matter hyperintensities (WMHs) are associated with symptom reporting and/or cognitive performance in 1202 active-duty service members with prior single or multiple mild traumatic brain injury (mTBI). Patients with mTBI evaluated at the National Intrepid Center of Excellence (NICoE) at Walter Reed National Military Medical Center (WRNMMC) were divided into those with (
Language	English
Publishing date	2021-06-09
Document type	Journal Article
ISSN	2689-288X
ISSN (online)	2689-288X
DOI	10.1089/neur.2021.0002
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Article ; Online: Phosphodiesterase-5 (PDE-5) Inhibitors as Therapy for Cerebrovascular Dysfunction in Chronic Traumatic Brain Injury.

Kalyani, Priyanka / Lippa, Sara M / Werner, J Kent / Amyot, Franck / Moore, Carol B / Kenney, Kimbra / Diaz-Arrastia, Ramon

Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics

2023 Volume 20, Issue 6, Page(s) 1629–1640

Abstract: Multiple phase III randomized controlled trials (RCTs) for pharmacologic interventions in traumatic brain injury (TBI) have failed despite promising results in experimental models. The heterogeneity of TBI, in terms of pathomechanisms and impacted brain ... ...

Abstract	Multiple phase III randomized controlled trials (RCTs) for pharmacologic interventions in traumatic brain injury (TBI) have failed despite promising results in experimental models. The heterogeneity of TBI, in terms of pathomechanisms and impacted brain structures, likely contributes to these failures. Biomarkers have been recommended to identify patients with relevant pathology (predictive biomarkers) and confirm target engagement and monitor therapy response (pharmacodynamic biomarkers). Our group focuses on traumatic cerebrovascular injury as an understudied endophenotype of TBI and is validating a predictive and pharmacodynamic imaging biomarker (cerebrovascular reactivity; CVR) in moderate-severe TBI. We aim to extend these studies to milder forms of TBI to determine the optimal dose of sildenafil for maximal improvement in CVR. We will conduct a phase II dose-finding study involving 160 chronic TBI patients (mostly mild) using three doses of sildenafil, a phosphodiesterase-5 (PDE-5) inhibitor. The study measures baseline CVR and evaluates the effect of escalating sildenafil doses on CVR improvement. A 4-week trial of thrice daily sildenafil will assess safety, tolerability, and clinical efficacy. This dual-site 4-year study, funded by the Department of Defense and registered in ClinicalTrials.gov (NCT05782244), plans to launch in June 2023. Biomarker-informed RCTs are essential for developing effective TBI interventions, relying on an understanding of underlying pathomechanisms. Traumatic microvascular injury (TMVI) is an attractive mechanism which can be targeted by vaso-active drugs such as PDE-5 inhibitors. CVR is a potential predictive and pharmacodynamic biomarker for targeted interventions aimed at TMVI. (Trial registration: NCT05782244, ClinicalTrials.gov ).
MeSH term(s)	Humans ; Phosphodiesterase 5 Inhibitors/therapeutic use ; Cyclic Nucleotide Phosphodiesterases, Type 5 ; Sildenafil Citrate/therapeutic use ; Cerebrovascular Circulation/physiology ; Brain Injuries, Traumatic/complications ; Brain Injuries, Traumatic/drug therapy ; Brain Injuries, Traumatic/pathology ; Biomarkers
Chemical Substances	Phosphodiesterase 5 Inhibitors ; Cyclic Nucleotide Phosphodiesterases, Type 5 (EC 3.1.4.35) ; Sildenafil Citrate (BW9B0ZE037) ; Biomarkers
Language	English
Publishing date	2023-09-11
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	2316693-9
ISSN	1878-7479 ; 1933-7213
ISSN (online)	1878-7479
ISSN	1933-7213
DOI	10.1007/s13311-023-01430-z
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Article ; Online: Cerebrovascular Reactivity Measurement with Functional Near Infrared Spectroscopy.

Amyot, Franck / Davis, Cora / Sangobowale, Mike / Moore, Carol / Silverman, Erika / Gandjbakhche, Amir / Diaz-Arrastia, Ramon / Kenney, Kimbra

Journal of visualized experiments : JoVE

2022 , Issue 184

Abstract: Cerebrovascular reactivity (CVR) is the capacity of blood vessels in the brain to alter cerebral blood flow (either with dilation or constriction) in response to chemical or physical stimuli. The amount of reactivity in the cerebral microvasculature ... ...

Abstract	Cerebrovascular reactivity (CVR) is the capacity of blood vessels in the brain to alter cerebral blood flow (either with dilation or constriction) in response to chemical or physical stimuli. The amount of reactivity in the cerebral microvasculature depends on the integrity of the capacitance vasculature and is the primary function of endothelial cells. CVR is, therefore, an indicator of the microvasculature's physiology and overall health. Imaging methods that can measure CVR are available but can be costly, and require magnetic resonance imaging centers and technical expertise. In this study, we used fNIRS technology to monitor changes of oxyhemoglobin (HbO) and deoxyhemoglobin (HbR) in the cerebral microvasculature to assess the CVR of 15 healthy controls (HC) in response to a vasoactive stimulus (inhaled 5% carbon dioxide or CO2). Our results suggest that this is a promising imaging technology that offers a non-invasive, accurate, portable, and cost-effective method of mapping cortical CVR and associated microvasculature function, resulting from a traumatic brain injury or other conditions associated with cerebral microvasculopathy.
MeSH term(s)	Brain/blood supply ; Brain/diagnostic imaging ; Carbon Dioxide ; Cerebrovascular Circulation/physiology ; Endothelial Cells ; Magnetic Resonance Imaging/methods ; Spectroscopy, Near-Infrared
Chemical Substances	Carbon Dioxide (142M471B3J)
Language	English
Publishing date	2022-06-02
Publishing country	United States
Document type	Journal Article ; Video-Audio Media ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2259946-0
ISSN	1940-087X ; 1940-087X
ISSN (online)	1940-087X
ISSN	1940-087X
DOI	10.3791/61284
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Article ; Online: Blood biomarkers of traumatic brain injury and cognitive impairment in older veterans.

Peltz, Carrie B / Kenney, Kimbra / Gill, Jessica / Diaz-Arrastia, Ramon / Gardner, Raquel C / Yaffe, Kristine

Neurology

2020 Volume 95, Issue 9, Page(s) e1126–e1133

Abstract: Objective: To determine whether blood-based biomarkers can differentiate older veterans with and without traumatic brain injury (TBI) and cognitive impairment (CogI).: Methods: We enrolled 155 veterans from 2 veterans' retirement homes: 90 without ... ...

Abstract	Objective: To determine whether blood-based biomarkers can differentiate older veterans with and without traumatic brain injury (TBI) and cognitive impairment (CogI). Methods: We enrolled 155 veterans from 2 veterans' retirement homes: 90 without TBI and 65 with TBI history. Participants were further separated into CogI groups: controls (no TBI, no CogI), n = 60; no TBI with CogI, n = 30; TBI without CogI, n = 30; and TBI with CogI, n = 35. TBI was determined by the Ohio State University TBI Identification Method. CogI was defined as impaired cognitive testing, dementia diagnosis, or use of dementia medication. Blood specimens were enriched for CNS-derived exosomes. Proteins (neurofilament light [NfL], total tau, glial fibrillary acidic protein [GFAP], α-synuclein, β-amyloid 42 [Aβ42], and phosphorylated tau [p-tau]) and cytokines (tumor necrosis factor-α [TNF-α], interleukin-6 [IL-6], and interleukin-10) were measured using ultrasensitive immunoassays. Results: Veterans were, on average, 79 years old. In participants with TBI history, 65% had mild TBI; average time from most recent TBI was 37 years. In adjusted analyses, the TBI and CogI groups differed on CNS-enriched exosome concentration of p-tau, NfL, IL-6, TNF-α (all Conclusions: Increased levels of blood-based, CNS-enriched exosomal biomarkers associated with TBI and CogI can be detected even decades after TBI. Classification of evidence: This study provides Class II evidence that in veterans with a history of TBI, CNS-enriched exosome concentration of p-tau, NfL, IL-6, and TNF-α are associated with CogI.
MeSH term(s)	Aged ; Aged, 80 and over ; Amyloid beta-Peptides/blood ; Biomarkers/blood ; Brain Injuries, Traumatic/blood ; Case-Control Studies ; Cognitive Dysfunction/blood ; Exosomes/metabolism ; Female ; Glial Fibrillary Acidic Protein/blood ; Humans ; Interleukin-10/blood ; Interleukin-6/blood ; Male ; Mental Status and Dementia Tests ; Neural Cell Adhesion Molecule L1/metabolism ; Neurofilament Proteins/blood ; Neuropsychological Tests ; Peptide Fragments/blood ; Phosphorylation ; Tumor Necrosis Factor-alpha/blood ; Veterans ; alpha-Synuclein/blood ; tau Proteins/blood
Chemical Substances	Amyloid beta-Peptides ; Biomarkers ; GFAP protein, human ; Glial Fibrillary Acidic Protein ; IL10 protein, human ; IL6 protein, human ; Interleukin-6 ; L1CAM protein, human ; MAPT protein, human ; Neural Cell Adhesion Molecule L1 ; Neurofilament Proteins ; Peptide Fragments ; SNCA protein, human ; TNF protein, human ; Tumor Necrosis Factor-alpha ; alpha-Synuclein ; amyloid beta-protein (1-42) ; neurofilament protein L ; tau Proteins ; Interleukin-10 (130068-27-8)
Language	English
Publishing date	2020-06-22
Publishing country	United States
Document type	Journal Article ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	207147-2
ISSN	1526-632X ; 0028-3878
ISSN (online)	1526-632X
ISSN	0028-3878
DOI	10.1212/WNL.0000000000010087
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Article: Headache among combat-exposed veterans and service members and its relation to mild traumatic brain injury history and other factors: a LIMBIC-CENC study.

Walker, William C / Clark, Sarah W / Eppich, Kaleb / Wilde, Elisabeth A / Martin, Aaron M / Allen, Chelsea M / Cortez, Melissa M / Pugh, Mary Jo / Walton, Samuel R / Kenney, Kimbra

Frontiers in neurology

2023 Volume 14, Page(s) 1242871

Abstract: Background: Headache (HA) is a common persistent complaint following mild traumatic brain injury (mTBI), but the association with remote mTBI is not well established, and risk factors are understudied.: Objective: Determine the relationship of mTBI ... ...

Abstract	Background: Headache (HA) is a common persistent complaint following mild traumatic brain injury (mTBI), but the association with remote mTBI is not well established, and risk factors are understudied. Objective: Determine the relationship of mTBI history and other factors with HA prevalence and impact among combat-exposed current and former service members (SMs). Design: Secondary cross-sectional data analysis from the Long-Term Impact of Military-Relevant Brain Injury Consortium-Chronic Effects of Neurotrauma Consortium prospective longitudinal study. Methods: We examined the association of lifetime mTBI history, demographic, military, medical and psychosocial factors with (1) HA prevalence ("lately, have you experienced headaches?") using logistic regression and (2) HA burden via the Headache Impact Test-6 (HIT-6) using linear regression. Each lifetime mTBI was categorized by mechanism (blast-related or not) and setting (combat deployed or not). Participants with non-credible symptom reporting were excluded, leaving Results: At a median 10 years since last mTBI, mTBI positive participants had higher HA prevalence (69% overall, 78% if 3 or more mTBIs) and greater HA burden (67% substantial/severe impact) than non-TBI controls (46% prevalence, 54% substantial/severe impact). In covariate-adjusted analysis, HA prevalence was higher with greater number of blast-related mTBIs (OR 1.81; 95% CI 1.48, 2.23), non-blast mTBIs while deployed (OR 1.42; 95% CI 1.14, 1.79), or non-blast mTBIs when not deployed (OR 1.23; 95% CI 1.02, 1.49). HA impact was only higher with blast-related mTBIs. Female identity, younger age, PTSD symptoms, and subjective sleep quality showed effects in both prevalence and impact models, with the largest mean HIT-6 elevation for PTSD symptoms. Additionally, combat deployment duration and depression symptoms were factors for HA prevalence, and Black race and Hispanic/Latino ethnicity were factors for HA impact. In sensitivity analyses, time since last mTBI and early HA onset were both non-significant. Conclusion: The prevalence of HA symptoms among formerly combat-deployed veterans and SMs is higher with more lifetime mTBIs regardless of how remote. Blast-related mTBI raises the risk the most and is uniquely associated with elevated HA burden. Other demographic and potentially modifiable risk factors were identified that may inform clinical care.
Language	English
Publishing date	2023-09-20
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2564214-5
ISSN	1664-2295
ISSN	1664-2295
DOI	10.3389/fneur.2023.1242871
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Article ; Online: Persistent MRI Findings Unique to Blast and Repetitive Mild TBI: Analysis of the CENC/LIMBIC Cohort Injury Characteristics.

Military medicine

2024

Abstract: Introduction: MRI represents one of the clinical tools at the forefront of research efforts aimed at identifying diagnostic and prognostic biomarkers following traumatic brain injury (TBI). Both volumetric and diffusion MRI findings in mild TBI (mTBI) ... ...

Abstract	Introduction: MRI represents one of the clinical tools at the forefront of research efforts aimed at identifying diagnostic and prognostic biomarkers following traumatic brain injury (TBI). Both volumetric and diffusion MRI findings in mild TBI (mTBI) are mixed, making the findings difficult to interpret. As such, additional research is needed to continue to elucidate the relationship between the clinical features of mTBI and quantitative MRI measurements. Material and methods: Volumetric and diffusion imaging data in a sample of 976 veterans and service members from the Chronic Effects of Neurotrauma Consortium and now the Long-Term Impact of Military-Relevant Brain Injury Consortium observational study of the late effects of mTBI in combat with and without a history of mTBI were examined. A series of regression models with link functions appropriate for the model outcome were used to evaluate the relationships among imaging measures and clinical features of mTBI. Each model included acquisition site, participant sex, and age as covariates. Separate regression models were fit for each region of interest where said region was a predictor. Results: After controlling for multiple comparisons, no significant main effect was noted for comparisons between veterans and service members with and without a history of mTBI. However, blast-related mTBI were associated with volumetric reductions of several subregions of the corpus callosum compared to non-blast-related mTBI. Several volumetric (i.e., hippocampal subfields, etc.) and diffusion (i.e., corona radiata, superior longitudinal fasciculus, etc.) MRI findings were noted to be associated with an increased number of repetitive mTBIs versus. Conclusions: In deployment-related mTBI, significant findings in this cohort were only observed when considering mTBI sub-groups (blast mechanism and total number/dose). Simply comparing healthy controls and those with a positive mTBI history is likely an oversimplification that may lead to non-significant findings, even in consortium analyses.
Language	English
Publishing date	2024-02-24
Publishing country	England
Document type	Journal Article
ZDB-ID	391061-1
ISSN	1930-613X ; 0026-4075
ISSN (online)	1930-613X
ISSN	0026-4075
DOI	10.1093/milmed/usae031
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Article ; Online: Relation of Aerobic Activity to Cognition and Well-being in Chronic Mild Traumatic Brain Injury: A LIMBIC-CENC Study.

Wright, Brennan M / Zhang, Chong / Fisher, Renae R / Karmarkar, Amol M / Bjork, James M / Pugh, Mary Jo / Hodges, Cooper B / Martindale, Sarah L / Wilde, Elisabeth A / Kenney, Kimbra / McDonald, Scott D / Scheibel, Randall S / Newsome, Mary R / Cook, Lawrence J / Walker, William C

Military medicine

2023 Volume 188, Issue Suppl 6, Page(s) 124–133

Abstract: Introduction: Because chronic difficulties with cognition and well-being are common after mild traumatic brain injury (mTBI) and aerobic physical activity and exercise (PAE) is a potential treatment and mitigation strategy, we sought to determine their ... ...

Abstract	Introduction: Because chronic difficulties with cognition and well-being are common after mild traumatic brain injury (mTBI) and aerobic physical activity and exercise (PAE) is a potential treatment and mitigation strategy, we sought to determine their relationship in a large sample with remote mTBI. Materials and methods: The Long-Term Impact of Military-Relevant Brain Injury Consortium-Chronic Effects of Neurotrauma Consortium prospective longitudinal study is a national multicenter observational study of combat-exposed service members and veterans. Study participants with positive mTBI histories (n = 1,087) were classified as "inactive" (23%), "insufficiently active" (46%), "active" (19%), or "highly active" (13%) based on the aerobic PAE level. The design was a cross-sectional analysis with multivariable regression. PAE was reported on the Behavioral Risk Factor Surveillance System. Preselected primary outcomes were seven well-validated cognitive performance tests of executive function, learning, and memory: The California Verbal Learning Test-Second Edition Long-Delay Free Recall and Total Recall, Brief Visuospatial Memory Test-Revised Total Recall, Trail-Making Test-Part B, and NIH Toolbox for the Assessment of Neurological Behavior and Function Cognition Battery Picture Sequence Memory, Flanker, and Dimensional Change Card Sort tests. Preselected secondary outcomes were standardized self-report questionnaires of cognitive functioning, life satisfaction, and well-being. Results: Across the aerobic activity groups, cognitive performance tests were not significantly different. Life satisfaction and overall health status scores were higher for those engaging in regular aerobic activity. Exploratory analyses also showed better working memory and verbal fluency with higher aerobic activity levels. Conclusions: An association between the aerobic activity level and the preselected primary cognitive performance outcome was not demonstrated using this study sample and methods. However, higher aerobic activity levels were associated with better subjective well-being. This supports a clinical recommendation for regular aerobic exercise among persons with chronic or remote mTBI. Future longitudinal analyses of the exercise-cognition relationship in chronic mTBI populations are recommended.
MeSH term(s)	Humans ; Brain Concussion/epidemiology ; Cross-Sectional Studies ; Prospective Studies ; Longitudinal Studies ; Neuropsychological Tests ; Cognition ; Veterans/psychology
Language	English
Publishing date	2023-11-10
Publishing country	England
Document type	Observational Study ; Multicenter Study ; Journal Article ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, Non-U.S. Gov't
ZDB-ID	391061-1
ISSN	1930-613X ; 0026-4075
ISSN (online)	1930-613X
ISSN	0026-4075
DOI	10.1093/milmed/usad056
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