Publications by authors named "Amy K Wagner"

132 Publications

Acute Cortisol Profile Associations With Cognitive Impairment After Severe Traumatic Brain Injury.

Neurorehabil Neural Repair 2021 Oct 23:15459683211048771. Epub 2021 Oct 23.

Department of Physical Medicine & Rehabilitation, 171669University of Pittsburgh, Pittsburgh, PA, USA.

Background: Cognitive impairments commonly occur after traumatic brain injury (TBI) and affect daily functioning. Cortisol levels, which are elevated during acute hospitalization for most individuals after severe TBI, can influence cognition, but this association has not been studied previously in TBI.

Objective: We hypothesized that serum and cerebral spinal fluid (CSF) cortisol trajectories over days 0-5 post-injury are associated with cognition 6-month post-injury.

Methods: We examined 94 participants with severe TBI, collected acute serum and/or CSF samples over days 0-5 post-injury, and compared cortisol levels to those in 17 healthy controls. N = 88 participants had serum, and n = 84 had CSF samples available for cortisol measurement and had neuropsychological testing 6 months post-injury. Group based trajectory analysis (TRAJ) was used to generate temporal serum and CSF cortisol profiles which were examined for associations with neuropsychological performance. We used linear regression to examine relationships between cortisol TRAJ groups and both overall and domain-specific cognition.

Results: TRAJ analysis identified a group and a group for serum and a group and group for CSF cortisol. Multivariable analysis showed serum cortisol TRAJ group was associated with overall cognitive composites scores ( = .024) and with executive function ( = .039) and verbal fluency ( = .029) domain scores. CSF cortisol TRAJ group was associated with overall cognitive composite scores ( = .021) and domain scores for executive function ( = .041), verbal fluency ( = .031), and attention ( = .034).

Conclusions: High acute cortisol trajectories are associated with poorer cognition 6 months post-TBI.
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http://dx.doi.org/10.1177/15459683211048771DOI Listing
October 2021

Early chronic systemic inflammation and associations with cognitive performance after moderate to severe TBI.

Brain Behav Immun Health 2021 Feb 15;11:100185. Epub 2020 Dec 15.

Department of Physical Medicine and Rehabilitation, School of Medicine, University of Pittsburgh, USA.

Background: Cognitive dysfunction adversely effects multiple functional outcomes and social roles after TBI. We hypothesize that chronic systemic inflammation exacerbates cognitive deficits post-injury and diminishes functional cognition and quality of life (QOL). Yet few studies have examined relationships between inflammation and cognition after TBI. Associations between early chronic serum inflammatory biomarker levels, cognitive outcomes, and QOL 6-months and 12-months after moderate-to-severe TBI were identified using unweighted (uILS) and weighted (wILS) inflammatory load score (ILS) formation.

Methods: Adults with moderate-to-severe TBI (n ​= ​157) completed neuropsychological testing, the Functional Impairment Measure Cognitive Subscale (FIM-Cog) and self-reported Percent Back to Normal scale 6 months (n ​= ​139) and 12 months (n ​= ​136) post-injury. Serial serum samples were collected 1-3 months post-TBI. Cognitive composite scores were created as equally weighted means of T-scores derived from a multidimensional neuropsychological test battery. Median inflammatory marker levels associated with 6-month and 12-month cognitive composite T-scores (p ​< ​0.10) were selected for ILS formation. Markers were quartiled, and quartile ranks were summed to generate an uILS. Marker-specific β-weights were derived using penalized ridge regression, multiplied by standardized marker levels, and summed to generate a wILS. ILS associations with cognitive composite scores were assessed using multivariable linear regression. Structural equation models assessed ILS influences on functional cognition and QOL using 12-month FIM-Cog and Percent Back to Normal scales.

Results: ILS component markers included: IL-1β, TNF-α, sIL-4R, sIL-6R, RANTES, and MIP-1β. Increased sIL-4R levels were positively associated with overall cognitive composite T-scores in bivariate analyses, while remaining ILS markers were negatively associated with cognition. Multivariable receiver operator curves (ROC) showed uILS added 14.98% and 31.93% relative improvement in variance captured compared to the covariates only base model (age, sex, education, Glasgow Coma Scale score) when predicting cognitive composite scores at 6 and 12 months, respectively; wILS added 33.99% and 36.87% relative improvement in variance captured. Cognitive composite mediated wILS associations with FIM-Cog scores at 12 months, and both cognitive composite and FIM-Cog scores mediated wILS associations with QOL.

Conclusions: Early chronic inflammatory burden is associated with cognitive performance post-TBI. wILS explains greater variance in cognitive composite T-scores than uILS. Linking inflammatory burden associated with cognitive deficits to functional outcome post-TBI demonstrates the potential impact of immunotherapy interventions aimed at improving cognitive recovery post-TBI.
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http://dx.doi.org/10.1016/j.bbih.2020.100185DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8474517PMC
February 2021

Early chronic systemic inflammation and associations with cognitive performance after moderate to severe TBI.

Brain Behav Immun Health 2021 Feb 15;11:100185. Epub 2020 Dec 15.

Department of Physical Medicine and Rehabilitation, School of Medicine, University of Pittsburgh, USA.

Background: Cognitive dysfunction adversely effects multiple functional outcomes and social roles after TBI. We hypothesize that chronic systemic inflammation exacerbates cognitive deficits post-injury and diminishes functional cognition and quality of life (QOL). Yet few studies have examined relationships between inflammation and cognition after TBI. Associations between early chronic serum inflammatory biomarker levels, cognitive outcomes, and QOL 6-months and 12-months after moderate-to-severe TBI were identified using unweighted (uILS) and weighted (wILS) inflammatory load score (ILS) formation.

Methods: Adults with moderate-to-severe TBI (n ​= ​157) completed neuropsychological testing, the Functional Impairment Measure Cognitive Subscale (FIM-Cog) and self-reported Percent Back to Normal scale 6 months (n ​= ​139) and 12 months (n ​= ​136) post-injury. Serial serum samples were collected 1-3 months post-TBI. Cognitive composite scores were created as equally weighted means of T-scores derived from a multidimensional neuropsychological test battery. Median inflammatory marker levels associated with 6-month and 12-month cognitive composite T-scores (p ​< ​0.10) were selected for ILS formation. Markers were quartiled, and quartile ranks were summed to generate an uILS. Marker-specific β-weights were derived using penalized ridge regression, multiplied by standardized marker levels, and summed to generate a wILS. ILS associations with cognitive composite scores were assessed using multivariable linear regression. Structural equation models assessed ILS influences on functional cognition and QOL using 12-month FIM-Cog and Percent Back to Normal scales.

Results: ILS component markers included: IL-1β, TNF-α, sIL-4R, sIL-6R, RANTES, and MIP-1β. Increased sIL-4R levels were positively associated with overall cognitive composite T-scores in bivariate analyses, while remaining ILS markers were negatively associated with cognition. Multivariable receiver operator curves (ROC) showed uILS added 14.98% and 31.93% relative improvement in variance captured compared to the covariates only base model (age, sex, education, Glasgow Coma Scale score) when predicting cognitive composite scores at 6 and 12 months, respectively; wILS added 33.99% and 36.87% relative improvement in variance captured. Cognitive composite mediated wILS associations with FIM-Cog scores at 12 months, and both cognitive composite and FIM-Cog scores mediated wILS associations with QOL.

Conclusions: Early chronic inflammatory burden is associated with cognitive performance post-TBI. wILS explains greater variance in cognitive composite T-scores than uILS. Linking inflammatory burden associated with cognitive deficits to functional outcome post-TBI demonstrates the potential impact of immunotherapy interventions aimed at improving cognitive recovery post-TBI.
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http://dx.doi.org/10.1016/j.bbih.2020.100185DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8474517PMC
February 2021

Research Needs for Prognostic Modeling and Trajectory Analysis in Patients with Disorders of Consciousness.

Neurocrit Care 2021 07 8;35(Suppl 1):55-67. Epub 2021 Jul 8.

Division of Neuroscience Critical Care, Departments of Anesthesiology and Critical Care Medicine and Neurology and Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Background: The current state of the science regarding the care and prognosis of patients with disorders of consciousness is limited. Scientific advances are needed to improve the accuracy, relevance, and approach to prognostication, thereby providing the foundation to develop meaningful and effective interventions.

Methods: To address this need, an interdisciplinary expert panel was created as part of the Coma Science Working Group of the Neurocritical Care Society Curing Coma Campaign.

Results: The panel performed a gap analysis which identified seven research needs for prognostic modeling and trajectory analysis ("recovery science") in patients with disorders of consciousness: (1) to define the variables that predict outcomes; (2) to define meaningful intermediate outcomes at specific time points for different endotypes; (3) to describe recovery trajectories in the absence of limitations to care; (4) to harness big data and develop analytic methods to prognosticate more accurately; (5) to identify key elements and processes for communicating prognostic uncertainty over time; (6) to identify health care delivery models that facilitate recovery and recovery science; and (7) to advocate for changes in the health care delivery system needed to advance recovery science and implement already-known best practices.

Conclusion: This report summarizes the current research available to inform the proposed research needs, articulates key elements within each area, and discusses the goals and advances in recovery science and care anticipated by successfully addressing these needs.
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http://dx.doi.org/10.1007/s12028-021-01289-yDOI Listing
July 2021

Plasma 1,3-β-d-glucan levels predict adverse clinical outcomes in critical illness.

JCI Insight 2021 07 22;6(14). Epub 2021 Jul 22.

Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA.

BACKGROUNDThe fungal cell wall constituent 1,3-β-d-glucan (BDG) is a pathogen-associated molecular pattern that can stimulate innate immunity. We hypothesized that BDG from colonizing fungi in critically ill patients may translocate into the systemic circulation and be associated with host inflammation and outcomes.METHODSWe enrolled 453 mechanically ventilated patients with acute respiratory failure (ARF) without invasive fungal infection and measured BDG, innate immunity, and epithelial permeability biomarkers in serially collected plasma samples.RESULTSCompared with healthy controls, patients with ARF had significantly higher BDG levels (median [IQR], 26 pg/mL [15-49 pg/mL], P < 0.001), whereas patients with ARF with high BDG levels (≥40 pg/mL, 31%) had higher odds for assignment to the prognostically adverse hyperinflammatory subphenotype (OR [CI], 2.88 [1.83-4.54], P < 0.001). Baseline BDG levels were predictive of fewer ventilator-free days and worse 30-day survival (adjusted P < 0.05). Integrative analyses of fungal colonization and epithelial barrier disruption suggested that BDG may translocate from either the lung or gut compartment. We validated the associations between plasma BDG and host inflammatory responses in 97 hospitalized patients with COVID-19.CONCLUSIONBDG measurements offered prognostic information in critically ill patients without fungal infections. Further research in the mechanisms of translocation and innate immunity recognition and stimulation may offer new therapeutic opportunities in critical illness.FUNDINGUniversity of Pittsburgh Clinical and Translational Science Institute, COVID-19 Pilot Award and NIH grants (K23 HL139987, U01 HL098962, P01 HL114453, R01 HL097376, K24 HL123342, U01 HL137159, R01 LM012087, K08HK144820, F32 HL142172, K23 GM122069).
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http://dx.doi.org/10.1172/jci.insight.141277DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8410081PMC
July 2021

Effect of CHRFAM7A Δ2bp gene variant on secondary inflammation after spinal cord injury.

PLoS One 2021 6;16(5):e0251110. Epub 2021 May 6.

School of Systems Biology, George Mason University, Fairfax, Virginia, United States of America.

The α7 neuronal nicotinic acetylcholine receptors (α7nAChRs) are essential for anti-inflammatory responses. The human-specific CHRFAM7A gene and its 2bp deletion polymorphism (Δ2bp variant) encodes a structurally-deficient α7nAChRs that may impact the anti-inflammatory function. We studied 45 spinal cord injury (SCI) patients for up to six weeks post SCI to investigate the role of the Δ2bp variant on multiple circulating inflammatory mediators and two outcome measures (neuropathic pain and risk of pressure ulcers). The patient's SCI were classified as either severe or mild. Missing values were imputed. Overall genetic effect was conducted with independent sample t-test and corrected with false discovery rate (FDR). Univariate analysis and regression analysis were applied to evaluate the Δ2bp effects on temporal variation of inflammatory mediators post SCI and their interaction with outcome measures. In severe SCI, the Δ2bp carriers showed higher levels of circulating inflammatory mediators than the Δ2bp non-carriers in TNF-α (FDR = 9.6x10-4), IFN-γ (FDR = 1.3x10-3), IL-13 (FDR = 1.6x10-3), CCL11 (FDR = 2.1x10-3), IL-12p70 (FDR = 2.2x10-3), IL-8 (FDR = 2.2x10-3), CXCL10 (FDR = 3.1x10-3), CCL4 (FDR = 5.7x10-3), IL-12p40 (FDR = 7.1x10-3), IL-1b (FDR = 0.014), IL-15 (FDR = 0.024), and IL-2 (FDR = 0.037). IL-8 and CCL2 were negatively associated with days post injury (DPI) for the Δ2bp carriers (P = 2x10-7 and P = 2x10-8, respectively) and IL-5 was positively associated with DPI for the Δ2bp non-carriers (P = 0.015). Neuropathic pain was marginally positively associated with IL-13 for the Δ2bp carriers (P = 0.056). In mild SCI, the Δ2bp carriers had lower circulating levels of IL-15 (FDR = 0.04) than the Δ2bp non-carriers. Temporal variation of inflammatory mediators post SCI was not associated with the Δ2bp variant. For the mild SCI Δ2bp carriers, risk of pressure ulcers was positively associated with circulating levels of IFN-γ, CXCL10, and CCL4 and negatively associated with circulating levels of IL-12p70. These findings support an important role for the human-specific CHRFAM7A Δ2bp gene variant in modifying anti-inflammatory function of α7nAChRs following SCI.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0251110PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8101719PMC
October 2021

Serum Biomarkers of Regeneration and Plasticity are Associated with Functional Outcome in Pediatric Neurocritical Illness: An Exploratory Study.

Neurocrit Care 2021 10 4;35(2):457-467. Epub 2021 Mar 4.

Department of Critical Care Medicine, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA, USA.

Background/objective: Pediatric neurocritical care survivorship is frequently accompanied by functional impairments. Lack of prognostic biomarkers is a barrier to early identification and management of impairment. We explored the association between blood biomarkers and functional impairment in children with acute acquired brain injury.

Methods: This study is a secondary analysis of a randomized control trial evaluating early versus usual care rehabilitation in the pediatric intensive care unit (PICU). Forty-four children (17 [39%] female, median age 11 [interquartile range 6-13] years) with acute acquired brain injury admitted to the PICU were studied. A single center obtained serum samples on admission days 0, 1, 3, 5, and the day closest to hospital discharge. Biomarkers relevant to brain injury (neuron specific enolase [NSE], S100b), inflammation (interleukin [IL-6], C-reactive protein), and regeneration (brain-derived neurotrophic factor [BDNF], vascular endothelial growth factor [VEGF]) were collected. Biomarkers were analyzed using a Luminex® bioassay. Functional status scale (FSS) scores were abstracted from the medical record. New functional impairment was defined as a (worse) FSS score at hospital discharge compared to pre-PICU (baseline). Individual biomarker fluorescence index (FI) values for each sample collection day were correlated with new functional impairment using Spearman rank correlation coefficient (ρ). Trends in repeated measures of biomarker FI over time were explored graphically, and the association between repeated measures of biomarker FI and new functional impairment was analyzed using covariate adjusted linear mixed-effect models.

Results: Functional impairment was inversely correlated with markers of regeneration and plasticity including BDNF at day 3 (ρ =  - 0.404, p = .015), day 5 (ρ =  - 0.549, p = 0.005) and hospital discharge (ρ =  - 0.420, p = 0.026) and VEGF at day 1 (ρ =  - 0.282, p = 0.008) and hospital discharge (ρ =  - 0.378, p = 0.047), such that lower levels of both markers at each time point were associated with greater impairment. Similarly, repeated measures of BDNF and VEGF were inversely correlated with new functional impairment (B =  - 0.001, p = 0.001 and B =  - 0.001, p = 0.003, respectively). NSE, a biomarker of acute brain injury, showed a positive correlation between day 0 levels and new functional impairment (ρ = 0.320, p = 0.044).

Conclusions: Blood-based biomarkers of regeneration and plasticity may hold prognostic utility for functional impairment among pediatric patients with neurocritical illness and warrant further investigation.
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http://dx.doi.org/10.1007/s12028-021-01199-zDOI Listing
October 2021

Determinants of caregiver burden in male patients with epilepsy following penetrating traumatic brain injury.

Epilepsy Behav 2021 03 7;116:107768. Epub 2021 Feb 7.

Cognitive Neuroscience Laboratory, Brain Injury Research, Think+Speak Lab, Shirley Ryan Ability Lab, Northwestern University, Chicago, IL, USA; Departments of Neurology, Psychiatry, and Cognitive Neurology & Alzheimer's Disease, Feinberg School of Medicine, Department of Psychology, Northwestern University, Chicago, IL, USA. Electronic address:

Purpose: We determined burden of caring for patients with post-traumatic epilepsy (PTE) following penetrating traumatic brain injury (TBI) and identified factors predicting higher burden.

Method: We assessed 331 caregiver-veteran dyads in Phase 2 (136 PTE, 136 non-PTE, and 59 HC dyads), 133 in Phase 4 (47 PTE, 56 non-PTE, and 30 HC dyads) - 30 years later, and 46 dyads in the follow-up study (18 PTE, 19 non-PTE, and 9 HC). Caregiver's burden was measured by Zarit Burden Index and a questionnaire. Veterans completed demographic, mental and physical well-being, quality-of-life, and medical-related information. Caregivers provided information about burden and their assessments of cognitive decline and neuropsychiatric status of the veterans.

Results: PTE caregivers perceived significantly more burden than comparison groups at all phases. Bivariate analyses revealed that caregiver distress due to the veteran's neuropsychiatric state including cognitive decline, apathy, and disinhibition and the veteran's characteristics including older age at epilepsy onset and role limitation due to physical problems were associated with higher burden. Finally, we revealed disinhibition distress, and role imitation due to physical problems as the predictors in a model of caregiver burden.

Conclusion: Elevated PTE caregiver burden is persistent across the life span suggesting that caregivers could benefit from counseling and targeted psychosocial interventions to reduce their burden.
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http://dx.doi.org/10.1016/j.yebeh.2021.107768DOI Listing
March 2021

Effects of an acute care brain injury medicine continuity consultation service on health care utilization and rehabilitation outcomes.

PM R 2021 11 5;13(11):1227-1236. Epub 2021 Apr 5.

Department of Physical Medicine and Rehabilitation, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

Introduction: Although general physiatry acute-care consultation services are commonplace and improve length of stay (LOS), the benefits of a subspecialty physiatric continuity consultation service targeting patients with severe brain injury have not been reported.

Objectives: Our primary objective was to characterize patient care recommendations from a Brain Injury Medicine (BIM) Continuity Consult Service, and to investigate the effects on acute-care LOS relative to brain injury patients receiving General Physical Medicine & Rehabilitation (PM&R) Consult Services. Our secondary objectives were to examine inpatient rehabilitation (IPR) health care utilization metrics and costs between groups and evaluate clinical improvements during IPR and discharge disposition.

Design: Retrospective cohort comparison study.

Setting: Academic medical center with level 1 trauma center.

Participants: Adults with severe brain injury admitted to a single-site acute-care facility and subsequently admitted to a single inpatient brain injury rehabilitation unit over the same time period.

Physiatric Care Models: BIM Continuity Consult Service versus General PM&R Consult Service.

Main Outcome Measures: Acute-care LOS; unplanned discharges to acute-care.

Results: Despite no major demographic or clinical group differences, the BIM Consult Service had more patient comorbidities than General PM&R Consult Service (17.5±5.3 versus 16±5.1;P = .04). BIM Consult Service patients spent fewer days in acute care (30±11.8 versus 36±22.8; P = .008), and early BIM consult (≤7 days after admission) was associated with shorter acute-care LOS (P < .002). IPR LOS was similar between groups when considering unplanned transfers. Unplanned transfers among General PM&R Consult Service patients occurred twice as frequently as in BIM Consult Service patients; average readmission costs were $2778 per patient on the BIM Consult Service and $6702 per patient on the General PM&R Consult Service. More BIM Consult Service (85.7%) than General PM&R Consult Service (27.3%) patients emerged from disorders of consciousness during IPR (P = .02).

Conclusions: BIM Continuity Consultation Services were associated with shorter acute-care LOS, fewer unplanned acute-care transfers, and an increased likelihood of emerging from a minimally conscious state during IPR.
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http://dx.doi.org/10.1002/pmrj.12563DOI Listing
November 2021

Treelet transform analysis to identify clusters of systemic inflammatory variance in a population with moderate-to-severe traumatic brain injury.

Brain Behav Immun 2021 07 30;95:45-60. Epub 2021 Jan 30.

Department of Physical Medicine and Rehabilitation, University of Pittsburgh, Pittsburgh, PA, USA; Safar Center for Resuscitation Research, University of Pittsburgh, Pittsburgh, PA, USA; Department of Neuroscience, University of Pittsburgh, Pittsburgh, PA, USA; Center for Neuroscience, University of Pittsburgh, Pittsburgh, PA, USA; Clinical and Translational Science Institute, University of Pittsburgh, Pittsburgh, PA, USA. Electronic address:

Background: Inflammatory cascades following traumatic brain injury (TBI) can have both beneficial and detrimental effects on recovery. Single biomarker studies do not adequately reflect the major arms of immunity and their relationships to long-term outcomes. Thus, we applied treelet transform (TT) analysis to identify clusters of interrelated inflammatory markers reflecting major components of systemic immune function for which substantial variation exists among individuals with moderate-to-severe TBI.

Methods: Serial blood samples from 221 adults with moderate-to-severe TBI were collected over 1-6 months post-injury (n = 607 samples). Samples were assayed for 33 inflammatory markers using Millipore multiplex technology. TT was applied to standardized mean biomarker values generated to identify latent patterns of correlated markers. Treelet clusters (TC) were characterized by biomarkers related to adaptive immunity (TC1), innate immunity (TC2), soluble molecules (TC3), allergy immunity (TC4), and chemokines (TC5). For each TC, a score was generated as the linear combination of standardized biomarker concentrations and cluster load for each individual in the cohort. Ordinal logistic or linear regression was used to test associations between TC scores and 6- and 12-month Glasgow Outcome Scale (GOS), Disability Rating Scale (DRS), and covariates.

Results: When adjusting for clinical covariates, TC5 was significantly associated with 6-month GOS (odds ratio, OR = 1.44; p-value, p = 0.025) and 6-month DRS scores (OR = 1.46; p = 0.013). TC5 relationships were attenuated when including all TC scores in the model (GOS: OR = 1.29, p = 0.163; DRS: OR = 1.33, p = 0.100). When adjusting for all TC scores and covariates, only TC3 was associated with 6- and 12-month GOS (OR = 1.32, p = 0.041; OR = 1.39, p = 0.002) and also 6- and 12-month DRS (OR = 1.38, p = 0.016; OR = 1.58, p = 0.0002). When applying TT to inflammation markers significantly associated with 6-month GOS, multivariate modeling confirmed that TC3 remained significantly associated with GOS. Biomarker cluster membership remained consistent between the GOS-specific dendrogram and overall dendrogram.

Conclusions: TT effectively characterized chronic, systemic immunity among a cohort of individuals with moderate-to-severe TBI. We posit that chronic chemokine levels are effector molecules propagating cellular immune dysfunction, while chronic soluble receptors are inflammatory damage readouts perpetuated, in part, by persistent dysfunctional cellular immunity to impact neuro-recovery.
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http://dx.doi.org/10.1016/j.bbi.2021.01.026DOI Listing
July 2021

Postoperative Treatment of Intracranial Hypotension Venous Congestion-Associated Brain Injury With Zolpidem.

Am J Phys Med Rehabil 2021 06;100(6):e89-e92

From the Department of Physical Medicine and Rehabilitation, University of Pittsburgh, Pittsburgh, Pennsylvania (LMD, KAM, AKW); University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania (AKW); Department of Neuroscience, University of Pittsburgh, Pittsburgh, Pennsylvania (AKW); Clinical and Translational Science Institute, University of Pittsburgh, Pittsburgh, Pennsylvania (AKW); Safar Center for Resuscitation Research, University of Pittsburgh, Pittsburgh, Pennsylvania (AKW); and Center for Neuroscience, University of Pittsburgh, Pittsburgh, Pennsylvania (AKW).

Abstract: A previously independent 75-yr-old man developed postoperative intracranial hypotension-associated venous congestion after an elective T10-pelvis fusion, which was complicated by durotomy. Postoperative day 0 magnetic resonance imaging noted symmetric edema of the basal ganglia, thalami, and cerebellar cortex as well as smooth diffuse pachymeningeal enhancement and dural thickening, consistent with postoperative intracranial hypotension-associated venous congestion. On postoperative day 0, patient developed tonic clonic seizures, and on postoperative day 2, patient was unable to follow commands or blink to visual threat, able to track eyes to sound only, and spontaneously moved all limbs. Patient was started on zolpidem 2.5 mg on postoperative day 2, and 12 hrs later, he had significantly improved motor function, arousal, verbalization, and followed simple commands. After three doses, patient was fully alert and oriented with improved mobility and comprehension. Six zolpidem doses were administered in total, and repeat magnetic resonance imaging on postoperative day 16 showed markedly improved regional edema. The patient was admitted to a brain injury inpatient rehabilitation unit and was discharged to home 9 days later with Functional Independence Measure gain of 17. Intracranial hypotension can adversely affect primary mesocircuit structures supporting arousal. Zolpidem, a selective α-1-subunit GABA-A agonist, supports GABAergic tone in these regions. This patient's clinical presentation and recovery paralleled selective basal ganglial-thalamic edema development and resolution.
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http://dx.doi.org/10.1097/PHM.0000000000001595DOI Listing
June 2021

Postoperative Treatment of Intracranial Hypotension Venous Congestion-Associated Brain Injury With Zolpidem.

Am J Phys Med Rehabil 2021 06;100(6):e89-e92

From the Department of Physical Medicine and Rehabilitation, University of Pittsburgh, Pittsburgh, Pennsylvania (LMD, KAM, AKW); University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania (AKW); Department of Neuroscience, University of Pittsburgh, Pittsburgh, Pennsylvania (AKW); Clinical and Translational Science Institute, University of Pittsburgh, Pittsburgh, Pennsylvania (AKW); Safar Center for Resuscitation Research, University of Pittsburgh, Pittsburgh, Pennsylvania (AKW); and Center for Neuroscience, University of Pittsburgh, Pittsburgh, Pennsylvania (AKW).

Abstract: A previously independent 75-yr-old man developed postoperative intracranial hypotension-associated venous congestion after an elective T10-pelvis fusion, which was complicated by durotomy. Postoperative day 0 magnetic resonance imaging noted symmetric edema of the basal ganglia, thalami, and cerebellar cortex as well as smooth diffuse pachymeningeal enhancement and dural thickening, consistent with postoperative intracranial hypotension-associated venous congestion. On postoperative day 0, patient developed tonic clonic seizures, and on postoperative day 2, patient was unable to follow commands or blink to visual threat, able to track eyes to sound only, and spontaneously moved all limbs. Patient was started on zolpidem 2.5 mg on postoperative day 2, and 12 hrs later, he had significantly improved motor function, arousal, verbalization, and followed simple commands. After three doses, patient was fully alert and oriented with improved mobility and comprehension. Six zolpidem doses were administered in total, and repeat magnetic resonance imaging on postoperative day 16 showed markedly improved regional edema. The patient was admitted to a brain injury inpatient rehabilitation unit and was discharged to home 9 days later with Functional Independence Measure gain of 17. Intracranial hypotension can adversely affect primary mesocircuit structures supporting arousal. Zolpidem, a selective α-1-subunit GABA-A agonist, supports GABAergic tone in these regions. This patient's clinical presentation and recovery paralleled selective basal ganglial-thalamic edema development and resolution.
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http://dx.doi.org/10.1097/PHM.0000000000001595DOI Listing
June 2021

Temporal Acute Serum Estradiol and Tumor Necrosis Factor-α Associations and Risk of Death after Severe Traumatic Brain Injury.

J Neurotrauma 2020 10 24;37(20):2198-2210. Epub 2020 Jun 24.

Department of Physical Medicine and Rehabilitation, University of Pittsburgh, Pittsburgh, Pennsylvania.

Severe traumatic brain injury (TBI) activates a robust systemic response that involves inflammatory and other factors, including estradiol (E2), associated with increased deaths. Tumor necrosis factor-alpha (TNFα) is a significant mediator of systemic shock, and it is an extra-gonadal transcription factor for E2 production. The study objectives were to test the hypotheses: (1) a positive feedback relationship exists between acute serum TNFα and E2; and (2) acute concentrations of E2 and TNFα are prognostic indicators of death after severe TBI. This prospective cohort study included N = 157 adults with severe TBI. Serum samples were collected for the first five days post-injury. The TNFα and E2 levels were averaged into two time epochs: first 72 h (T1) and second 72 h post-injury (T2). A cross-lag panel analysis conducted between T1 and T2 TNFα and E2 levels showed significant cross-lag effects: T1 TNFα and T1 E2 were related to T2 E2 and T2 TNFα, respectively. Cox proportional hazards multi variable regression models determined that increases in T1 E2 (hazard ratio [HR] = 1.79, 95% confidence interval [CI]: 1.15, 2.81), but not T2 E2 (HR = 0.91, 95% CI: 0.56, 1.47), were associated with increased risk of death. Increased T2 TNFα (HR = 2.47, 95% CI: 1.35, 4.53), and T1 TNFα (HR = 1.47, 95% CI: 0.99, 2.19), to a lesser degree, were associated with increased risk of death. Relationships of death with T2 TNFα and T1 E2 were mediated partially by cardiovascular, hepatic, and renal dysfunction. Both E2 and TNFα are systemic, reciprocally related biomarkers that may be indicative of systemic compromise and increased risk of death after severe TBI.
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http://dx.doi.org/10.1089/neu.2019.6577DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7580589PMC
October 2020

Anti-Pituitary and Anti-Hypothalamus Autoantibody Associations with Inflammation and Persistent Hypogonadotropic Hypogonadism in Men with Traumatic Brain Injury.

J Neurotrauma 2020 07 13;37(14):1609-1626. Epub 2020 Apr 13.

Department of Physical Medicine & Rehabilitation, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.

Traumatic brain injury (TBI) and can lead to persistent hypogonadotropic hypogonadism (PHH) and poor outcomes. We hypothesized that autoimmune and inflammatory mechanisms contribute to PHH pathogenesis. Men with moderate-to-severe TBI ( = 143) were compared with healthy men ( = 39). The TBI group provided blood samples 1-12 months post-injury ( = 1225). TBI and healthy control ( = 39) samples were assayed for testosterone (T) and luteinizing hormone (LH) to adjudicate PHH status. TBI samples 1-6 months post-injury and control samples were assayed for immunoglobulin M (IgM)/immunoglobulin G (IgG) anti-pituitary autoantibodies (APA) and anti-hypothalamus autoantibodies (AHA). Tissue antigen specificity for APA and AHA was confirmed via immunohistochemistry (IHC). IgM and IgG autoantibodies for glial fibrillary acid protein (GFAP) (AGA) were evaluated to gauge APA and AHA production as a generalized autoimmune response to TBI and to evaluate the specificity of APA and AHA to PHH status. An inflammatory marker panel was used to assess relationships to autoantibody profiles and PHH status. Fifty-one men with TBI (36%) had PHH. An age-related decline in T levels by both TBI and PHH status were observed. Injured men had higher APA IgM, APA IgG, AHA IgM, AHA IgG, AGA IgM, and AGA IgG than controls ( < 0.0001 all comparisons). However, only APA IgM ( = 0.03) and AHA IgM ( = 0.03) levels were lower in the PHH than in the non-PHH group in multivariate analysis. There were no differences in IgG levels by PHH status. Multiple inflammatory markers were positively correlated with IgM autoantibody production. PHH was associated with higher soluble tumor-necrosis-factor receptors I/II, (sTNFRI, sTNFRII), regulated on activation, normal T-cell expressed and secreted (RANTES) and soluble interleukin-2-receptor-alpha (sIL-2Rα) levels. Higher IgM APA, and AHA, but not AGA, in the absence of PHH may suggest a beneficial or reparative role for neuroendocrine tissue-specific IgM autoantibody production against PHH development post-TBI.
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http://dx.doi.org/10.1089/neu.2019.6780DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7336882PMC
July 2020

Interrelationships Between Post-TBI Employment and Substance Abuse: A Cross-lagged Structural Equation Modeling Analysis.

Arch Phys Med Rehabil 2020 05 7;101(5):797-806. Epub 2019 Dec 7.

Department of Physical Medicine and Rehabilitation, University of Pittsburgh, Pittsburgh, Pennsylvania; Center for Neuroscience, University of Pittsburgh, Pittsburgh, Pennsylvania; Safar Center of Resuscitation Research, University of Pittsburgh, Pittsburgh, Pennsylvania; Department of Neuroscience, University of Pittsburgh, Pittsburgh, Pennsylvania; Clinical and Translational Science Institute, University of Pittsburgh, Pittsburgh, Pennsylvania. Electronic address:

Objective: To describe the interrelationship of postinjury employment and substance abuse (SA) among individuals with traumatic brain injury.

Design: Structural equation model (SEM) and logistic regression analytic approach using a merged database of the National Trauma Data Bank (NTDB) and Traumatic Brain Injury Model Systems (TBIMS) National Database, with acute care and rehabilitation hospitalization data and 1, 2, and 5 year follow-up data.

Setting: United States Level I/II trauma centers and inpatient rehabilitation centers with telephone follow-up.

Participants: Individuals in the TBIMS National Database successfully matched to their NTDB data, aged 18-59 years, with trauma severity, age, sex, employment, and SA data at 1, 2, and/or 5 years postinjury (N=2890).

Interventions: Not applicable.

Main Outcome Measure: Employment status (employed/unemployed) and SA (present/absent) at year 1, year 2, and year 5 postinjury.

Results: SEM analysis showed older age at injury predicted lower likelihood of employment at all time points postinjury (β=-0.016; β=-0.006; β=-0.016; all P<.001), while higher injury severity score (ISS) predicted lower likelihood of employment (β=-0.008; P=.027) and SA (β=-0.007; P=.050) at year 1. Male sex predicted higher likelihood of SA at each follow-up (β=0.227; β=0.184; β=0.161; all P<.100). Despite associations of preinjury unemployment with higher preinjury SA, postinjury employment at year 1 predicted SA at year 2 (β=0.118; P=.028). Employment and SA during the previous follow-up period predicted subsequent employment and SA, respectively.

Conclusions: Employment and SA have unique longitudinal interrelationships and are additionally influenced by age, sex, and ISS. The present work suggests the need for more research on causal, confounding, and mediating factors and appropriate screening and intervention tools that minimize SA and facilitate successful employment-related outcomes.
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http://dx.doi.org/10.1016/j.apmr.2019.10.189DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7183422PMC
May 2020

Effects of hospital-acquired pneumonia on long-term recovery and hospital resource utilization following moderate to severe traumatic brain injury.

J Trauma Acute Care Surg 2020 04;88(4):491-500

From the Department of Epidemiology (R.G.K., M.M.B., A.F.), Department of Physical Medicine and Rehabilitation (R.G.K., M.R.K., A.K.W.), and Department of Surgery (M.R.K., J.S.), University of Pittsburgh, Pittsburgh, Pennsylvania; Department of Physical Medicine and Rehabilitation (S.B.J.), and Department of Rehabilitation Counseling (S.B.J.), UT Southwestern, Dallas, Texas; Department of Epidemiology (M.M.B), University of Pittsburgh, Pittsburgh, Pennsylvania; Department of Rehabilitation Medicine (K.D.-O.'C.), and Department of Neurology (K.D.-O.'C.), Icahn School of Medicine at Mount Sinai, New York, New York; Department of Internal Medicine Epidemiology Division (M.J.P.), University of Utah, Salt Lake City, Utah; Clinical and Translational Science Institute (A.K.W.), Center for Neuroscience, University of Pittsburgh, Pittsburgh, Pennsylvania, and Safar Center for Resuscitation Research (A.K.W.), University of Pittsburgh, Pittsburgh, Pennsylvania.

Background: Individuals with traumatic brain injury (TBI) have extended inpatient hospital stays that include prolonged mechanical ventilation, increasing risk for infections, including pneumonia. Studies show the negative short-term effects of hospital-acquired pneumonia (HAP) on hospital-based outcomes; however, little is known of its long-term effects.

Methods: A prospective cohort study was conducted. National Trauma Databank and Traumatic Brain Injury Model Systems were merged to derive a cohort of 3,717 adults with moderate-to-severe TBI. Exposure data were gathered from the National Trauma Databank, and outcomes were gathered from the Traumatic Brain Injury Model Systems. The primary outcome was the Glasgow Outcome Scale-Extended (GOS-E), which was collected at 1, 2, and 5 years postinjury. The GOS-E was categorized as favorable (>5) or unfavorable (≤5) outcomes. A generalized estimating equation model was fitted estimating the effects of HAP on GOS-E over the first 5 years post-TBI, adjusting for age, race, ventilation status, brain injury severity, injury severity score, thoracic Abbreviated Injury Scale score of 3 or greater, mechanism of injury, intraventricular hemorrhage, and subarachnoid hemorrhage.

Results: Individuals with HAP had a 34% (odds ratio, 1.34; 95% confidence interval, 1.15-1.56) increased odds for unfavorable GOS-E over the first 5 years post-TBI compared with individuals without HAP, after adjustment for covariates. There was a significant interaction between HAP and follow-up, such that the effect of HAP on GOS-E declined over time. Sensitivity analyses that weighted for nonresponse bias and adjusted for differences across trauma facilities did not appreciably change the results. Individuals with HAP spent 10.1 days longer in acute care and 4.8 days longer in inpatient rehabilitation and had less efficient functional improvement during inpatient rehabilitation.

Conclusion: Individuals with HAP during acute hospitalization have worse long-term prognosis and greater hospital resource utilization. Preventing HAP may be cost-effective and improve long-term recovery for individuals with TBI. Future studies should compare the effectiveness of different prophylaxis methods to prevent HAP.

Level Of Evidence: Prospective cohort study, level III.
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http://dx.doi.org/10.1097/TA.0000000000002562DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7802881PMC
April 2020

Altered White Matter Integrity after Mild to Moderate Traumatic Brain Injury.

J Clin Med 2019 Aug 27;8(9). Epub 2019 Aug 27.

Department of Rehabilitation Medicine, Seoul National University Hospital, Seoul 03080, Korea.

(1) Background: White matter changes among individuals with mild-to-moderate traumatic brain injury (TBI) may be sensitive imaging markers reflecting functional impairment, particularly in the context of post-concussion syndrome. The objective of this study was to examine the altered white matter integrity in mild-to-moderate TBI patients compared with age-matched normal controls. (2) Methods: Diffusion tensor imaging data from 15 individuals with TBI and 15 control subjects were retrospectively obtained. We investigated and compared white matter integrity in both groups, with regard to fractional anisotropy (FA), radial diffusivity (RD), and axial diffusivity (AD) and examined the relationship with cognitive dysfunction and impaired balance in patients. (3) Results: In comparison with controls, the TBI patients had significantly decreased FA as well as increased RD, in the right corticospinal tract. Decreased RD was observed in the left cerebellar area near the middle cerebellar peduncle. Decreased AD was observed in the left inferior cerebellar peduncle, showing positive correlation with poor balance control. We observed decreased FA and increased AD in the left superior longitudinal fasciculus showing positive and negative correlation, respectively, with cognitive function in the TBI group. (4) Conclusions: Altered white matter integrity in mild-to-moderate TBI cases may be indicative of cognitive dysfunction and impaired balance.
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http://dx.doi.org/10.3390/jcm8091318DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6780936PMC
August 2019

Extended (10-Day) Real-Time Monitoring by Dexamethasone-Enhanced Microdialysis in the Injured Rat Cortex.

ACS Chem Neurosci 2019 08 27;10(8):3521-3531. Epub 2019 Jun 27.

Department of Chemistry , University of Pittsburgh , Pittsburgh , Pennsylvania 15260 , United States.

Intracerebral microdialysis has proven useful for chemical monitoring in patients following traumatic brain injury. Recent studies in animals, however, have documented that insertion of microdialysis probes into brain tissues initiates a foreign-body response. Within a few days after probe insertion, the foreign body response impedes the use of microdialysis to monitor the K and glucose transients associated with spreading depolarization, a potential mechanism for secondary brain injury. Herein, we show that perfusing microdialysis probes with dexamethasone, a potent anti-inflammatory glucocorticoid, suppresses the foreign body response and facilitates the monitoring of spontaneous spreading depolarizations for at least 10 days following controlled cortical injury in the rat. In addition to spreading depolarizations, results of this study suggest that a progressive, apparently permanent, decline in pericontusional interstitial glucose may be an additional sequela of brain injury. This study establishes extended dexamethasone-enhanced microdialysis in the injured rodent cortex as a new paradigm for investigating trauma-induced metabolic crisis.
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http://dx.doi.org/10.1021/acschemneuro.9b00145DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7341684PMC
August 2019

Association of a Functional Polymorphism in the Gene with Inflammatory Response Mediators and Neuropathic Pain after Spinal Cord Injury.

J Neurotrauma 2019 11 23;36(21):3026-3033. Epub 2019 May 23.

School of Systems Biology, George Mason University, Fairfax, Virginia.

The alpha 7 nicotinic acetylcholine receptor, α7 nAChR, plays a central role in regulating inflammatory responses. Previous studies showed that pharmacological inhibitors of α7nAChR have a pro-inflammatory effect, increasing the circulating levels of cytokines such as tumor necrosis factor alpha (TNFα). This study focused on how genetic polymorphisms of the partially duplicated α7nAChR gene (), which is highly expressed in peripheral blood cells, contribute to functional outcome after spinal cord injury (SCI). In a cohort of 27 SCI patients and 25 emergency room consented controls (% F/M: 15/85, 24/76; mean ± SE age: 35 ± 1.38 and 35 ± 2.0 respectively), a panel of circulating cytokines, noradrenergic metabolite (normetanephrine [NMN]) levels, and clinical data were available within the first 7 days post-injury (DPI) up to 90 DPI, and were investigated in the acute/subacute (DPI 1-21) and intermediate (DPI 22-90) temporal periods. Cytokine and NMN plasma levels on different DPI were analyzed as a function of genotype. TNFα levels, as a representative of some elevated inflammatory mediators, were nearly threefold higher in individuals carrying the del-2bp variant of the gene compared with that in the no-deletion genotype ( = 0.001 analysis of variance [ANOVA]) 3 weeks DPI, and twofold higher than genotype-matched acute/subacute non-SCI injury controls within 7 days DPI. In contrast, NMN levels were initially unchanged, although after 3 weeks, NMN levels were significantly decreased in SCI individuals carrying the del-2bp variant compared with non-carriers ( = 0.011 ANOVA). Numerical pain scores over this same period post-injury were significantly elevated in SCI patients carrying the del-2bp variant relative to non-carriers ( = 0.001 ANOVA). Taken together, these data reveal that pro-inflammatory responses associated with gene variation may also be associated with differences in pain experience in patients following SCI, at least during the intermediate phase.
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http://dx.doi.org/10.1089/neu.2018.6200DOI Listing
November 2019

A Repeated Measures Pilot Comparison of Trajectories of Fluctuating Endogenous Hormones in Young Women with Traumatic Brain Injury, Healthy Controls.

Behav Neurol 2019 12;2019:7694503. Epub 2019 Feb 12.

Department of Physical Medicine and Rehabilitation, University of Pittsburgh, PA, USA.

Objective: To compare baseline and 72-hour hormone levels in women with traumatic brain injury (TBI) and controls.

Setting: Hospital emergency department.

Participants: 21 women ages 18-35 with TBI and 21 controls.

Design: Repeated measures.

Main Measures: Serum samples at baseline and 72 hours; immunoassays for estradiol (E2), progesterone (PRO), luteinizing hormone (LH), follicle-stimulating hormone (FSH), and cortisol (CORT); and health history.

Results: Women with TBI had lower E2 ( = 0.042) and higher CORT ( = 0.028) levels over time. Lower Glasgow Coma Scale (GSC) and OCs were associated with lower FSH (GCS = 0.021; OCs = 0.016) and higher CORT (GCS = 0.001; OCs = 0.008).

Conclusion: Acute TBI may suppress E2 and increase CORT in young women. OCs appeared to independently affect CORT and FSH responses. Future work is needed with a larger sample to characterize TBI effects on women's endogenous hormone response to injury and OC use's effects on post-TBI stress response and gonadal function, as well as secondary injury.
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http://dx.doi.org/10.1155/2019/7694503DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6390250PMC
July 2019

Variability in daily self-reported emotional symptoms and fatigue measured over eight weeks in community dwelling individuals with traumatic brain injury.

Brain Inj 2019 5;33(5):567-573. Epub 2019 Mar 5.

e Department of Physical Medicine and Rehabilitation , University of Pittsburgh , Pittsburgh , PA , USA.

Objective: To investigate within-person variability in daily self-reported emotional and fatigue symptoms and factors associated with high within-person variability among individuals with chronic traumatic brain injury (TBI).

Design: This was a prospective descriptive pilot study of n = 18 adults with chronic TBI (2-27 years post-injury) who owned and could independently use an Apple or Android device.

Methods: Participants completed daily assessments for 8 weeks via smartphone. Outcome measures included the Positive and Negative Affect Schedule, Patient Health Questionnaire-2, Generalized Anxiety Disorder-2, and a 7-point fatigue rating. We examined within-person variability over time using individual Multilevel Linear Models. We categorized within-person variability as High or Low based on individual standard deviations in relationship to sample standard deviation.

Results: Significant temporal within-person variability occurred for all measures. High variability was associated with more symptom reporting versus Low variability, and variability was associated with sex (High variability: 88% women; Low variability 90% men).

Conclusions: Symptom measurement at a single time point among adults with chronic TBI may not capture day-to-day symptom fluctuation and may misidentify individuals in need of intervention. Assessing symptom profiles over time to capture temporal and individual variability may provide a more ecologically valid measure for managing long-term symptoms after TBI.
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http://dx.doi.org/10.1080/02699052.2019.1584333DOI Listing
April 2020

Comorbid Conditions Among Adults 50 Years and Older With Traumatic Brain Injury: Examining Associations With Demographics, Healthcare Utilization, Institutionalization, and 1-Year Outcomes.

J Head Trauma Rehabil 2019 Jul/Aug;34(4):224-232

Departments of Physical Medicine & Rehabilitation (Drs Kumar, Olsen, and Wagner) and Epidemiology (Dr Kumar), Clinical and Translational Science Institute, Center for Neuroscience, and Safar Center for Resuscitation Research (Dr Wagner), University of Pittsburgh, Pennsylvania; Departments of Physical Medicine and Rehabilitation (Dr Juengst) and Rehabilitation Counseling (Dr Juengst), UT Southwestern, Dallas, Texas; Department of Rehabilitation and Human Performance and Department of Neurology, Icahn School of Medicine at Mount Sinai, New York (Dr Dams-O'Connor); Department of Communication Sciences and Disorders, Northeastern University, Boston, Massachusetts (Dr O'Neil-Pirozzi); Department of Physical Medicine and Rehabilitation, Spaulding Rehabilitation Hospital, Harvard Medical School, Boston, Massachusetts (Dr O'Neil-Pirozzi); and Department of Physical Medicine and Rehabilitation, Indiana University School of Medicine, Indianapolis (Dr Hammond).

Objectives: To assess the relationship of acute complications, preexisting chronic diseases, and substance abuse with clinical and functional outcomes among adults 50 years and older with moderate-to-severe traumatic brain injury (TBI).

Design: Prospective cohort study.

Participants: Adults 50 years and older with moderate-to-severe TBI (n = 2134).

Measures: Clusters of comorbid health conditions empirically derived from non-injury International Classification of Diseases, Ninth Revision codes, demographic/injury variables, and outcome (acute and rehabilitation length of stay [LOS], Functional Independence Measure efficiency, posttraumatic amnesia [PTA] duration, institutionalization, rehospitalization, and Glasgow Outcome Scale-Extended (GOS-E) at 1 year).

Results: Individuals with greater acute hospital complication burden were more often middle-aged men, injured in motor vehicle accidents, and had longer LOS and PTA. These same individuals experienced higher rates of 1-year rehospitalization and greater odds of unfavorable GOS-E scores at 1 year. Those with greater chronic disease burden were more likely to be rehospitalized at 1 year. Individuals with more substance abuse burden were most often younger (eg, middle adulthood), black race, less educated, injured via motor vehicle accidents, and had an increased risk for institutionalization.

Conclusion: Preexisting health conditions and acute complications contribute to TBI outcomes. This work provides a foundation to explore effects of comorbidity prevention and management on TBI recovery in older adults.
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http://dx.doi.org/10.1097/HTR.0000000000000470DOI Listing
October 2020

Association of Very Early Serum Levels of S100B, Glial Fibrillary Acidic Protein, Ubiquitin C-Terminal Hydrolase-L1, and Spectrin Breakdown Product with Outcome in ProTECT III.

J Neurotrauma 2019 10 9;36(20):2863-2871. Epub 2019 Jul 9.

Department of Emergency Medicine, Emory University School of Medicine and Grady Hospital, Atlanta, Georgia.

Rapid risk-stratification of patients with acute traumatic brain injury (TBI) would inform management decisions and prognostication. The objective of this serum biomarker study (Biomarkers of Injury and Outcome [BIO]-Progesterone for Traumatic Brain Injury, Experimental Clinical Treatment [ProTECT]) was to test the hypothesis that serum biomarkers of structural brain injury, measured at a single, very early time-point, add value beyond relevant clinical covariates when predicting unfavorable outcome 6 months after moderate-to-severe acute TBI. BIO-ProTECT utilized prospectively collected samples obtained from subjects with moderate-to-severe TBI enrolled in the ProTECT III clinical trial of progesterone. Serum samples were obtained within 4 h after injury. Glial fibrillary acidic protein (GFAP), S100B, αII-spectrin breakdown product of molecular weight 150 (SBDP150), and ubiquitin C-terminal hydrolase-L1 (UCH-L1) were measured. The association between log-transformed biomarker levels and poor outcome, defined by a Glasgow Outcome Scale-Extended (GOS-E) score of 1-4 at 6 months post-injury, were estimated via logistic regression. Prognostic models and a biomarker risk score were developed using bootstrapping techniques. Of 882 ProTECT III subjects, samples were available for 566. Each biomarker was associated with 6-month GOS-E ( < 0.001). Compared with a model containing baseline patient variables/characteristics, inclusion of S100B and GFAP significantly improved prognostic capacity ( ≤ 0.05 both comparisons); conversely, UCH-L1 and SBDP did not. A final predictive model incorporating baseline patient variables/characteristics and biomarker data (S100B and GFAP) had the best prognostic capability (area under the curve [AUC] = 0.85, 95% confidence interval [CI]: CI 0.81-0.89). Very early measurements of brain-specific biomarkers are independently associated with 6-month outcome after moderate-to-severe TBI and enhance outcome prediction.
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http://dx.doi.org/10.1089/neu.2018.5809DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6761588PMC
October 2019

Experimental traumatic brain injury results in estrous cycle disruption, neurobehavioral deficits, and impaired GSK3β/β-catenin signaling in female rats.

Exp Neurol 2019 05 31;315:42-51. Epub 2019 Jan 31.

NeuroBehavioral Research Laboratory, Department of Veterans Affairs, New Jersey Health Care System, East Orange, NJ, USA; Graduate School of Biomedical Sciences, Rutgers Biomedical and Health Sciences, 65 Bergen Street, Newark, NJ 07103, USA; Department of Pharmacology, Physiology and Neuroscience, New Jersey Medical School, Rutgers Biomedical and Health Science, Newark, NJ, USA. Electronic address:

An estimated 2.8 million traumatic brain injuries (TBI) occur within the United States each year. Approximately 40% of new TBI cases are female, however few studies have investigated the effects of TBI on female subjects. In addition to typical neurobehavioral sequelae observed after TBI, such as poor cognition, impaired behavior, and somatic symptoms, women with TBI report amenorrhea or irregular menstrual cycles suggestive of disruptions in the hypothalamic-pituitary-gonadal (HPG) axis. HPG dysfunction following TBI has been linked to poor functional outcome in men and women, but the mechanisms by which this may occur or relate to behavior has not been fully developed or ascertained. The present study determined if TBI resulted in HPG axis perturbations in young adult female Sprague Dawley rats, and whether TBI was associated with cognitive and sensorimotor deficits. Following lateral fluid percussion injury, injured females spent significantly more time in diestrus compared to sham females, consistent with a persistent low sex-steroid hormone state. Injured females displayed significantly reduced 17β-estradiol (E2) and luteinizing hormone levels. Concomitantly, injured females were impaired in spatial working memory compared to shams. Impaired GSK3β/β-catenin signaling related to synaptic changes was evident one-week post-injury in the hippocampus among injured females compared to sham females, and this impairment paralleled the deficits in spatial working memory. Sensorimotor function, as evidenced by suppression of the acoustic startle response, was chronically impaired even after normal estrous cycling resumed. These data demonstrate that TBI results in estrous cycle impairments, memory dysfunction, and perturbations in GSK3β/β-catenin signaling, suggesting a potential mechanism for HPG-mediated cognitive impairment following TBI.
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http://dx.doi.org/10.1016/j.expneurol.2019.01.017DOI Listing
May 2019

A mathematical model of neuroinflammation in severe clinical traumatic brain injury.

J Neuroinflammation 2018 Dec 18;15(1):345. Epub 2018 Dec 18.

Department of Mathematics, University of Pittsburgh, 301 Thackeray Hall, Pittsburgh, PA, 15260, USA.

Background: Understanding the interdependencies among inflammatory mediators of tissue damage following traumatic brain injury (TBI) is essential in providing effective, patient-specific care. Activated microglia and elevated concentrations of inflammatory signaling molecules reflect the complex cascades associated with acute neuroinflammation and are predictive of recovery after TBI. However, clinical TBI studies to date have not focused on modeling the dynamic temporal patterns of simultaneously evolving inflammatory mediators, which has potential in guiding the design of future immunomodulation intervention studies.

Methods: We derived a mathematical model consisting of ordinary differential equations (ODE) to represent interactions between pro- and anti-inflammatory cytokines, M1- and M2-like microglia, and central nervous system (CNS) tissue damage. We incorporated variables for several cytokines, interleukin (IL)-1β, IL-4, IL-10, and IL-12, known to have roles in microglial activation and phenotype differentiation. The model was fit to cerebrospinal fluid (CSF) cytokine data, collected during the first 5 days post-injury in n = 89 adults with severe TBI. Ensembles of model fits were produced for three patient subgroups: (1) a favorable outcome group (GOS = 4,5) and (2) an unfavorable outcome group (GOS = 1,2,3) both with lower pro-inflammatory load, and (3) an unfavorable outcome group (GOS = 1,2,3) with higher pro-inflammatory load. Differences in parameter distributions between subgroups were ranked using Bhattacharyya metrics to identify mechanistic differences underlying the neuroinflammatory patterns of patient groups with different TBI outcomes.

Results: Optimal model fits to data showed different microglial and damage responses by patient subgroup. Upon comparison of model parameter distributions, unfavorable outcome groups were characterized by either a prolonged, pathophysiological or a transient, sub-physiological course of neuroinflammation.

Conclusion: By developing a mathematical characterization of inflammatory processes informed by clinical data, we have created a system for exploring links between acute neuroinflammatory components and patient outcome in severe TBI.
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http://dx.doi.org/10.1186/s12974-018-1384-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6299616PMC
December 2018

Paths to Successful Translation of New Therapies for Severe Traumatic Brain Injury in the Golden Age of Traumatic Brain Injury Research: A Pittsburgh Vision.

J Neurotrauma 2020 11 1;37(22):2353-2371. Epub 2019 Feb 1.

Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.

New neuroprotective therapies for severe traumatic brain injury (TBI) have not translated from pre-clinical to clinical success. Numerous explanations have been suggested in both the pre-clinical and clinical arenas. Coverage of TBI in the lay press has reinvigorated interest, creating a golden age of TBI research with innovative strategies to circumvent roadblocks. We discuss the need for more robust therapies. We present concepts for traditional and novel approaches to defining therapeutic targets. We review lessons learned from the ongoing work of the pre-clinical drug and biomarker screening consortium Operation Brain Trauma Therapy and suggest ways to further enhance pre-clinical consortia. Biomarkers have emerged that empower choice and assessment of target engagement by candidate therapies. Drug combinations may be needed, and it may require moving beyond conventional drug therapies. Precision medicine may also link the right therapy to the right patient, including new approaches to TBI classification beyond the Glasgow Coma Scale or anatomical phenotyping-incorporating new genetic and physiologic approaches. Therapeutic breakthroughs may also come from alternative approaches in clinical investigation (comparative effectiveness, adaptive trial design, use of the electronic medical record, and big data). The full continuum of care must also be represented in translational studies, given the important clinical role of pre-hospital events, extracerebral insults in the intensive care unit, and rehabilitation. TBI research from concussion to coma can cross-pollinate and further advancement of new therapies. Misconceptions can stifle/misdirect TBI research and deserve special attention. Finally, we synthesize an approach to deliver therapeutic breakthroughs in this golden age of TBI research.
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http://dx.doi.org/10.1089/neu.2018.6203DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7698994PMC
November 2020

Factor structure of the Behavioral Assessment Screening Tool (BAST) in traumatic brain injury.

Disabil Rehabil 2020 01 17;42(2):255-260. Epub 2018 Nov 17.

Department of Physical Medicine and Rehabilitation, University of Pittsburgh, Pittsburgh, PA, USA.

Establish the factor structure of the Behavioral Assessment Screening Tool (BAST), a self-reported emotional/behavioral symptom measure for adults with traumatic brain injury (TBI). Community. Community-dwelling adults with moderate-severe TBI ( = 162;  = 110). Assessment development (cohort study). Behavioral Assessment Screening Tool. The original BAST included 61 items (55 primary, six secondary), an Environmental Context checklist including recent major life events, and three open-ended questions about other relevant factors. Two rounds of pilot testing and exploratory factor analysis of the BAST ( = 162;  = 110) reduced the total items to 37 primary items and six secondary coping items. The final BAST had a five-factor solution with communalities ranging from 0.323 to 0.771. Internal consistency reliabilities ranged from acceptable to excellent for all factors (Cronbach's  = 0.76-0.90). The items related to coping, given only to those endorsing stress, had a two-factor solution with communalities ranging from 0.224 to 0.605, but demonstrated acceptable to poor internal consistency (Cronbach's  = 0.46-0.68). Participants rated ease of use and overall satisfaction with completing the scale as high, with mean scores of 6.42 and 6.22 out of 7, respectively. The BAST, a measure of behavioral and emotional symptoms after TBI, has a multidimensional factor structure with evidence of good internal consistency reliability. Future work will evaluate the convergent, discriminant, and discriminative validity of the BAST and employ item response theory analyses to further develop a short version for mobile health assessment.Implications for RehabilitationLong-term monitoring of behavioral and emotional symptoms after traumatic brain injury could improve clinical management and reduce negative participation and quality of life outcomes.The Behavioral Assessment Screening Tool demonstrates reliability for use among adults with chronic traumatic brain injury, through its factor structure and internal consistency reliabilities, to measure chronic behavioral and emotional symptoms.The Behavioral Assessment Screening Tool is a screening tool to identify potential behavioral and emotional problems that individuals with chronic traumatic brain injury may be experiencing; it could be implemented in a proactive, rather than reactive, system for long-term monitoring of these symptoms to improve early identification of clinical disorders.
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http://dx.doi.org/10.1080/09638288.2018.1496487DOI Listing
January 2020

Employment Stability in the First 5 Years After Moderate-to-Severe Traumatic Brain Injury.

Arch Phys Med Rehabil 2019 03 26;100(3):412-421. Epub 2018 Jul 26.

Department of Physical Medicine and Rehabilitation, University of Pittsburgh, Pittsburgh, Pennsylvania; Center for Neuroscience, University of Pittsburgh, Pittsburgh, Pennsylvania; Safar Center of Resuscitation Research, University of Pittsburgh, Pittsburgh, Pennsylvania. Electronic address:

Objective: To characterize employment stability and identify predictive factors of employment stability in working-age individuals after moderate-to-severe traumatic brain injury (TBI) that may be clinically addressed.

Design: Longitudinal observational study of an inception cohort from the Traumatic Brain Injury Model Systems National Database (TBIMS-NDB) using data at years 1, 2, and 5 post-TBI.

Setting: Inpatient rehabilitation centers with telephone follow-up.

Participants: Individuals enrolled in the TBIMS-NDB since 2001, aged 18-59, with employment data at 2 or more follow-up interviews at years 1, 2, and 5 (N=5683).

Interventions: Not applicable.

Main Outcome Measure: Employment stability, categorized using post-TBI employment data as no paid employment (53.25%), stably (27.20%), delayed (10.24%), or unstably (9.31%) employed.

Results: Multinomial regression analyses identified predictive factors of employment stability, including younger age, white race, less severe injuries, preinjury employment, higher annual earnings, male sex, higher education, transportation independence postinjury, and no anxiety or depression at 1 year post-TBI.

Conclusions: Employment stability serves as an important measure of productivity post-TBI. Psychosocial, clinical, environmental, and demographic factors predict employment stability post-TBI. Notable predictors include transportation independence as well as the presence of anxiety and depression at year 1 post-TBI as potentially modifiable intervention targets.
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http://dx.doi.org/10.1016/j.apmr.2018.06.022DOI Listing
March 2019

Craniectomy and Craniotomy in Traumatic Brain Injury: A Propensity-Matched Analysis of Long-Term Functional and Quality of Life Outcomes.

World Neurosurg 2018 Oct 24;118:e974-e981. Epub 2018 Jul 24.

Department of Physical Medicine and Rehabilitation, Neuroscience, Safar Center for Resuscitation Research, Center for Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.

Objective: To report the comprehensive long-term functional and quality of life outcomes after craniectomy (CE) and craniotomy (CO) in individuals with traumatic brain injury (TBI).

Methods: Information on all individuals with TBI who had undergone CE or CO were extracted from the TBI Model Systems database from 2002 to 2012. A 1:1 propensity matching with replacement technique was used to balance the baseline characteristics across groups. The matched sample was analyzed for outcomes during hospitalization, acute rehabilitation, and ≤2 years of follow-up.

Results: We identified 1470 individuals who had undergone CE or CO. Individuals undergoing CE compared with CO demonstrated a longer length of stay in the hospital (median, 22 vs. 18 days; P < 0.0001) and acute rehabilitation (median 26 vs. 21 days; P < 0.0001). Individuals with CE had required rehospitalization more often by the 1-year follow-up point (39% vs. 25%; P < 0.0001) for reasons other than cranioplasty, including seizures (12% vs. 8%; P < 0.0001), neurologic events (i.e., hydrocephalus; 9% vs. 4%; P < 0.0001), and infections (10% vs 6%; P < 0.0001). Individuals with CE had significantly greater impairment using the Glasgow Outcome Scale-Extended, required more supervision, and were less likely to be employed at 1 and 2 years after TBI. No difference was observed in the satisfaction with life scale scores at 2 years. The Kaplan-Meier mortality estimates at 1 and 2 years showed no differences between the 2 groups (hazard ratio, 0.57; P = 0.4).

Conclusion: In a matched cohort, individuals undergoing CE compared with CO after TBI had a longer length of stay, decreased functional status, and more rehospitalizations. The survival at 2 years and the satisfaction with life scale scores were similar.
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http://dx.doi.org/10.1016/j.wneu.2018.07.124DOI Listing
October 2018
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