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40 APOE x BDNF Genetic Interaction is Associated with Poorer Cognitive Outcomes in Veterans with Histories of mTBI
- Adan F. Ton-Loy, Victoria C. Merritt, Erin D Ozturk, Monica Ly, Alin Alshaheri, Scott F. Sorg, Lisa Delano-Wood
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- Journal:
- Journal of the International Neuropsychological Society / Volume 29 / Issue s1 / November 2023
- Published online by Cambridge University Press:
- 21 December 2023, pp. 147-148
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Objective:
Many Operation Enduring Freedom/Operation Iraqi Freedom (OEF/OIF) Veterans have sustained a mild traumatic brain injury (mTBI) during their military service and a substantial “miserable minority” frequently report significant cognitive complaints long after injury. Although existing studies have shown associations between genetic factors (e.g., apolipoprotein E [APOE] and brain-derived neurotrophic factor [BDNF]) and cognitive performance in this vulnerable population, the TBI-genetics literature has generally been varied and inconsistent. Although past findings suggest that individuals who possess APOE £4 and BDNF Met alleles have worse cognitive outcomes after mTBI, this has not been consistently reported. Additionally, the influence of any gene-by-gene interactions on cognition has not been sufficiently explored and therefore remains a critical area of interest. Thus, we examined relationships between APOE and BDNF genotypes on neuropsychological function in a well-characterized sample of younger Veterans with mTBI histories.
Participants and Methods:Participants included Veterans with a history of mTBI who adequately completed performance validity testing. In total, 78 Veterans (84.6% male; age: M=32.95, SD=7.00; race/ethnicity: 51.3% White, 28.2% Hispanic/Latino, and 20.5% Another Race/Ethnicity) completed a structured clinical interview to collect detailed information on TBI history and underwent a comprehensive neuropsychological exam. A buccal swab was also collected to determine APOE and BDNF allele status for each participant. Three cognitive composite scores were computed reflecting memory (8 items), attention/processing speed (7 items), and executive functioning (10 items). Two-way analyses of covariance (ANCOVAs) adjusting for age, sex, and race/ethnicity were used to assess the effects of APOE (ε4+ vs. ε4-) and BDNF (Met+ vs. Met-) on cognitive functioning (ε4+/Met-: n=12, ε4+/Met+: n=8, £4-/Met-: n=35, and ε4-/Met+: n=23).
Results:ANCOVAs revealed no significant main effects for APOE or BDNF genotypes on cognitive functioning; however, there was a significant APOE x BDNF genotype interaction for all three cognitive composites (memory: p=.026, np2=.068; attention/processing speed: p=.045, np2=.055; and executive functioning: p=.031, np2=.064). Specifically, the interaction was such that Veterans in the ε4+/Met+ group demonstrated the poorest cognitive functioning relative to all other allele group combinations (ε4+/Met-, ε4-/Met+, ε4-/Met-).
Conclusions:The results of this preliminary study demonstrate that, compared to the other genetic subgroups in the TBI sample, Veterans with APOE £4 and BDNF Met alleles demonstrated the poorest cognitive functioning across several domains known to be negatively affected in the context of head injury (i.e., memory, attention/processing speed, and executive functioning). These findings are the first to show an APOE x BDNF interaction in Veterans with histories of mTBI. Further
research is necessary to replicate and extend this study in larger samples. Moreover, future work should incorporate neuroimaging variables to better interrogate structural and functional correlates of these observed genetic polymorphism associations in Veterans with mTBI histories.
2 Examining the Role of Symptom Attribution on Neurobehavioral and Neurocognitive Outcomes in Treatment-Seeking Veterans with Remote History of Traumatic Brain Injury
- Victoria C Merritt, McKenna S Sakamoto, Laura D Crocker, Amy J Jak
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- Journal:
- Journal of the International Neuropsychological Society / Volume 29 / Issue s1 / November 2023
- Published online by Cambridge University Press:
- 21 December 2023, pp. 667-668
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Objective:
Illness perception, or the ways in which individuals understand and cope with injury, has been extensively studied in the broader medical literature and has been found to have important associations with clinical outcomes across a wide range of medical conditions. However, there is a dearth of knowledge regarding how perceptions of traumatic brain injury (TBI) influence outcome and recovery following injury, especially in military populations. The purpose of this study was to examine relationships between illness perception, as measured via symptom attribution, and neurobehavioral and neurocognitive outcomes in Veterans with TBI history.
Participants and Methods:This cross-sectional study included 44 treatment-seeking Veterans (86.4% male, 65.9% white) with remote history of TBI (75.0% mild TBI). All Veterans were referred to the TBI Cognitive Rehabilitation Clinic at VA San Diego and completed a clinical interview, self-report questionnaires, and a neuropsychological assessment. A modified version of the Neurobehavioral Symptom Inventory (NSI) was administered to assess neurobehavioral symptom endorsement and symptom attribution. Symptom attribution was assessed by having participants rate whether they believe each NSI item was caused by TBI. A total symptom attribution score was computed, as well as the standard NSI total and symptom cluster scores (i.e., vestibular, somatic, cognitive, and affective symptom domains). Three cognitive composite scores (representing mean performance) were also computed, including memory, attention/processing speed, and executive functioning. Participants were excluded if they did not complete the NSI attribution questions or they failed performance validity testing.
Results:Results showed that the symptoms most frequently attributed to TBI included forgetfulness (82%), poor concentration (80%), and slowed thinking (77%). There was a significant positive association between symptom attribution and the NSI total score (r = 0.62, p < .001), meaning that greater attribution of symptoms to TBI was significantly associated with greater symptom endorsement overall.
Symptom attribution was also significantly associated with all four NSI symptom domains (r’s = 0.47-0.66; all p’s < .001), with the strongest relationship emerging between symptom attribution and vestibular symptoms. Finally, linear regressions demonstrated that symptom attribution but not symptom endorsement was significantly associated with objective cognitive functioning. Specifically, greater attribution of symptoms to TBI was associated with worse memory (ß = -0.33, p = .035) and attention/processing speed (ß = -0.40, p = .013) performance.
Conclusions:Results showed significant associations between symptom attribution and (1) symptom endorsement and (2) objective cognitive performance in Veterans with a remote history of TBI. Taken together, findings suggest that Veterans who attribute neurobehavioral symptoms to their TBI are at greater risk of experiencing poor long-term outcomes. Although more research is needed to understand how illness perception influences outcomes in this population, results highlight the importance of early psychoeducation regarding the anticipated course of recovery following TBI.
56 TBI Severity Moderates the Association between Subjective and Objective Attention in Older Veterans
- Peter P Rantins, Monica Ly, Alexandra L Clark, Alexandra J Weigand, Kayla S Walker, Victoria C Merritt, Katherine J Bangen, Kelsey R Thomas
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- Journal:
- Journal of the International Neuropsychological Society / Volume 29 / Issue s1 / November 2023
- Published online by Cambridge University Press:
- 21 December 2023, pp. 363-364
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Objective:
Prior work on associations between self-reported cognition and objective cognitive performance in Veterans has yielded mixed findings, with some evidence indicating that mild traumatic brain injury (TBI) may not impact the associations between subjective and objective cognition. However, few studies have examined these relationships in both mild and moderate-to-severe TBI, in older Veterans, and within specific cognitive domains. Therefore, we assessed the moderating effect of TBI severity on subjective and objective cognition across multiple cognitive domains.
Participants and Methods:This study included 246 predominately male Vietnam-Era Veterans (age M=69.61, SD=4.18, Range = 60.87 – 85.16) who completed neuropsychological testing and symptom questionnaires as part of the Department of Defense-Alzheimer’s Disease Neuroimaging Initiative (DoD-ADNI). Participants were classified as having history of no TBI (n=81), mild TBI (n=80), or moderate-tosevere TBI (n=85). Neuropsychological composite scores in the domains of memory, attention/executive functioning, and language were included as the outcome variables. The Everyday Cognition (ECog) measure was used to capture subjective cognition and, specifically, the ECog domain scores of memory, divided attention, and language were chosen as independent variables to mirror the objective cognitive domains. General linear models, adjusting for age, education, apolipoprotein E ε4 carrier status, pulse pressure, depressive symptom severity, and PTSD symptom severity, tested whether TBI severity moderated the associations of domain-specific subjective and objective cognition.
Results:Across the sample, subjective memory was associated with objective memory (β=-.205, 95% CI [-.332, -.078], p=.002) and subjective language was associated with objective language (β=-.267, 95% CI [-.399, -.134], p<.001). However, the main effect of subjective divided attention was not associated with objective attention/executive functioning (p=.124). The main effect of TBI severity was not associated with any of the objective cognitive domain scores after adjusting for the other variables in the model. The TBI severity x subjective cognition interaction was significant for attention/executive functioning [F(2,234)=5.18, p=.006]. Specifically, relative to Veterans without a TBI, participants with mild TBI (β=-.311, 95% CI [-.620, -.002], p=.048) and moderate-to-severe TBI (β=-.499, 95% CI [-.806, -.193], p=.002) showed stronger negative associations between subjective divided attention and objective attention/executive functioning. TBI severity did not moderate the associations between subjective and objective cognition for memory or language domains. The pattern of results did not change when the total number of TBIs was included in the models.
Conclusions:In this DoD-ADNI sample, stronger associations between subjective and objective attention were evident among individuals with mild and moderate-to-severe TBI compared to Veterans without a TBI history. Attention/executive functioning measures (Trails A and B) may be particularly sensitive to detecting subtle cognitive difficulties related to TBI and/or comorbid psychiatric symptoms, which may contribute to these attention-specific findings. The strongest associations were among those with moderate-to-severe TBI, potentially because the extent to which their attention difficulties are affecting their daily lives are more apparent despite no significant differences in objective attention performance by TBI group. This study highlights the importance of assessing both subjective and objective cognition in older Veterans and the particular relevance of the attention domain within the context of TBI.
48 Elevated Postconcussive Symptoms are Associated with Increased Anterior Cerebral Blood Flow and Not Cortical Thickness in Veterans with a History of Remote mTBI
- Erin D Ozturk, Victoria C Merritt, Monica T Ly, Alexandra L Clark, Katherine J Bangen, Adan F. Ton-Loy, Lisa Delano-Wood
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- Journal:
- Journal of the International Neuropsychological Society / Volume 29 / Issue s1 / November 2023
- Published online by Cambridge University Press:
- 21 December 2023, pp. 154-155
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Objective:
Veterans with a history of mild traumatic brain injury (mTBI) often endorse enduring postconcussive symptoms (PCS) including cognitive and neuropsychiatric complaints. However, although several studies have shown associations between these complaints and brain structure and cerebrovascular function, few studies have examined relationships between structural and functional brain alterations and PCS in the context of remote mTBI. We therefore examined whether PCS were associated with cortical thickness and cerebral blood flow (CBF) in a well-characterized sample of Veterans with a history of mTBI.
Participants and Methods:116 Veterans underwent structural neuroimaging and a clinical interview to obtain detailed TBI history and injury-related information. Participants also completed the following self-report measures: the Neurobehavioral Symptom Inventory (NSI) for ratings of cognitive, emotional, somatic-sensory, and vestibular symptoms, and the Posttraumatic Stress Disorder (PTSD) Checklist for PTSD symptom severity. Regional brain thickness was indexed using FreeSurfer-derived cortical parcellations of frontal and temporal regions of interest (ROIs) including the superior frontal gyrus (SFG), middle frontal gyrus (MFG), inferior frontal gyrus (IFG), orbitofrontal cortex (OFC), anterior cingulate cortex (ACC), medial temporal lobe (MTL), and lateral temporal lobe (LTL). A subset of Veterans (n=50) also underwent multi-phase pseudo-continuous arterial spin labeling (MPPCASL) to obtain resting CBF. T1-weighted structural and MPPCASL scans were co-registered and CBF estimates were extracted from the 7 bilateral parcellations of ROIs. To assess the relationship between NSI total and subscale scores and ROI thickness and CBF, multiple regression analyses were conducted adjusting for age, sex, and PTSD symptom severity. False Discovery Rate was used to correct for multiple comparisons.
Results:NSI total and subscale scores were not associated with cortical thickness of any ROI. However, higher NSI scores were associated with increased ROI CBF of the SFG (q=.014) and MFG CBF (q=.014). With respect to symptom subscales, higher affective subscale scores were associated with increased SFG (q=.001), MFG (q=.001), IFG (q=.039), ACC (q=.026), and LTL CBF (q=.026); higher cognitive subscale scores were associated with increased SFG (q=.014) and MFG CBF (q=.032); and higher vestibular subscale scores were associated with increased ACC CBF (q=.021). NSI somatic-sensory subscale scores were not associated with ROI CBF.
Conclusions:Results demonstrate that in TBI-susceptible anterior ROIs, alterations in CBF but not cortical thickness are associated with postconcussive symptomatology in Veterans with a history of mTBI. Specifically, postconcussive total symptoms as well as affective, cognitive, and vestibular subscale symptoms were strongly linked primarily to CBF of frontal regions. Remarkably, these results indicate that enduring symptoms in generally younger samples of Veterans with head injury histories may be closely tied to cerebrovascular function rather than brain structure changes. These findings may provide a neurological basis for negative clinical outcomes (e.g., enduring PCS and poor quality of life) that is frequently reported by many individuals following mTBI. Future work is needed to examine unique effects of blast exposure as well as associations with repeated injury on brain-behavior relationships.
Elevated Intraindividual Variability in Executive Functions and Associations with White Matter Microstructure in Veterans with Mild Traumatic Brain Injury
- Scott F. Sorg, Victoria C. Merritt, Alexandra L. Clark, Madeleine L. Werhane, Kelsey A. Holiday, Dawn M. Schiehser, Mark Bondi, Lisa Delano-Wood
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- Journal:
- Journal of the International Neuropsychological Society / Volume 27 / Issue 4 / April 2021
- Published online by Cambridge University Press:
- 24 September 2020, pp. 305-314
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Objective:
We examined whether intraindividual variability (IIV) across tests of executive functions (EF-IIV) is elevated in Veterans with a history of mild traumatic brain injury (mTBI) relative to military controls (MCs) without a history of mTBI. We also explored relationships among EF-IIV, white matter microstructure, and posttraumatic stress disorder (PTSD) symptoms.
Method:A total of 77 Veterans (mTBI = 43, MCs = 34) completed neuropsychological testing, diffusion tensor imaging (DTI), and PTSD symptom ratings. EF-IIV was calculated as the standard deviation across six tests of EF, along with an EF-Mean composite. DSI Studio connectometry analysis identified white matter tracts significantly associated with EF-IIV according to generalized fractional anisotropy (GFA).
Results:After adjusting for EF-Mean and PTSD symptoms, the mTBI group showed significantly higher EF-IIV than MCs. Groups did not differ on EF-Mean after adjusting for PTSD symptoms. Across groups, PTSD symptoms significantly negatively correlated with EF-Mean, but not with EF-IIV. EF-IIV significantly negatively correlated with GFA in multiple white matter pathways connecting frontal and more posterior regions.
Conclusions:Veterans with mTBI demonstrated significantly greater IIV across EF tests compared to MCs, even after adjusting for mean group differences on those measures as well as PTSD severity. Findings suggest that, in contrast to analyses that explore effects of mean performance across tests, discrepancy analyses may capture unique variance in neuropsychological performance and more sensitively capture cognitive disruption in Veterans with mTBI histories. Importantly, findings show that EF-IIV is negatively associated with the microstructure of white matter pathways interconnecting cortical regions that mediate executive function and attentional processes.
Loss of Consciousness is Associated with Elevated Cognitive Intra-Individual Variability Following Sports-Related Concussion
- Victoria C. Merritt, Liora S. Greenberg, Jessica E. Meyer, Peter A. Arnett
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- Journal:
- Journal of the International Neuropsychological Society / Volume 27 / Issue 2 / February 2021
- Published online by Cambridge University Press:
- 10 August 2020, pp. 197-203
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Objective:
The purpose of this study was to evaluate whether loss of consciousness (LOC), retrograde amnesia (RA), and anterograde amnesia (AA) independently influence a particular aspect of post-concussion cognitive functioning—across-test intra-individual variability (IIV), or cognitive dispersion.
Method:Concussed athletes (N = 111) were evaluated, on average, 6.04 days post-injury (SD = 5.90; Mdn = 4 days; Range = 1–26 days) via clinical interview and neuropsychological assessment. Primary outcomes of interest included two measures of IIV—an intra-individual standard deviation (ISD) score and a maximum discrepancy (MD) score—computed from 18 norm-referenced variables.
Results:Analyses of covariance (ANCOVAs) adjusting for time since injury and sex revealed a significant effect of LOC on the ISD (p = .018, ηp2 = .051) and MD (p = .034, ηp2 = .041) scores, such that athletes with LOC displayed significantly greater IIV than athletes without LOC. In contrast, measures of IIV did not significantly differ between athletes who did and did not experience RA or AA (all p > .05).
Conclusions:LOC, but not RA or AA, was associated with greater variability, or inconsistencies, in cognitive performance acutely following concussion. Though future studies are needed to verify the clinical significance of these findings, our results suggest that LOC may contribute to post-concussion cognitive dysfunction and may be a risk factor for less efficient cognitive functioning.
Psychological Symptoms and Rates of Performance Validity Improve Following Trauma-Focused Treatment in Veterans with PTSD and History of Mild-to-Moderate TBI
- Sarah M. Jurick, Laura D. Crocker, Victoria C. Merritt, Samantha N. Hoffman, Amber V. Keller, Graham M. L. Eglit, Kelsey R. Thomas, Sonya B. Norman, Dawn M. Schiehser, Carie S. Rodgers, Elizabeth W. Twamley, Amy J. Jak
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- Journal:
- Journal of the International Neuropsychological Society / Volume 26 / Issue 1 / January 2020
- Published online by Cambridge University Press:
- 29 October 2019, pp. 108-118
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Objective:
Iraq and Afghanistan Veterans with posttraumatic stress disorder (PTSD) and traumatic brain injury (TBI) history have high rates of performance validity test (PVT) failure. The study aimed to determine whether those with scores in the invalid versus valid range on PVTs show similar benefit from psychotherapy and if psychotherapy improves PVT performance.
Method:Veterans (N = 100) with PTSD, mild-to-moderate TBI history, and cognitive complaints underwent neuropsychological testing at baseline, post-treatment, and 3-month post-treatment. Veterans were randomly assigned to cognitive processing therapy (CPT) or a novel hybrid intervention integrating CPT with TBI psychoeducation and cognitive rehabilitation strategies from Cognitive Symptom Management and Rehabilitation Therapy (CogSMART). Performance below standard cutoffs on any PVT trial across three different PVT measures was considered invalid (PVT-Fail), whereas performance above cutoffs on all measures was considered valid (PVT-Pass).
Results:Although both PVT groups exhibited clinically significant improvement in PTSD symptoms, the PVT-Pass group demonstrated greater symptom reduction than the PVT-Fail group. Measures of post-concussive and depressive symptoms improved to a similar degree across groups. Treatment condition did not moderate these results. Rate of valid test performance increased from baseline to follow-up across conditions, with a stronger effect in the SMART-CPT compared to CPT condition.
Conclusion:Both PVT groups experienced improved psychological symptoms following treatment. Veterans who failed PVTs at baseline demonstrated better test engagement following treatment, resulting in higher rates of valid PVTs at follow-up. Veterans with invalid PVTs should be enrolled in trauma-focused treatment and may benefit from neuropsychological assessment after, rather than before, treatment.
Beyond Measures of Central Tendency: Novel Methods to Examine Sex Differences in Neuropsychological Performance Following Sports-Related Concussion in Collegiate Athletes
- Victoria C. Merritt, Liora S. Greenberg, Erin Guty, Megan L. Bradson, Amanda R. Rabinowitz, Peter A. Arnett
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- Journal:
- Journal of the International Neuropsychological Society / Volume 25 / Issue 10 / November 2019
- Published online by Cambridge University Press:
- 03 September 2019, pp. 1094-1100
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Objective:
The purpose of this study was to examine sex differences in neuropsychological functioning after sports-related concussion using several approaches to assess cognition: mean performance, number of impaired scores, and intraindividual variability (IIV).
Method:In the study, 152 concussed college athletes were administered a battery of neuropsychological tests, on average, 10 days post-concussion (SD = 12.75; Mdn = 4 days; Range = 0–72 days). Mean performance was evaluated across 18 individual neuropsychological variables, and the total number of impaired test scores (>1.5 SD below the mean) was calculated for each athlete. Two measures of IIV were also computed: an intraindividual standard deviation (ISD) score and a maximum discrepancy (MD) score.
Results:Analyses of covariance revealed that, compared with males, females had significantly more impaired scores and showed greater variability on both IIV indices (ISD and MD scores) after adjusting for time since injury and post-concussive symptoms. In contrast, no significant effects of sex were found when examining mean neuropsychological performance.
Conclusion:Although females and males demonstrated similar mean performance following concussion, females exhibited a greater level of cognitive impairment and larger inconsistencies in cognitive performance than males. These results suggest that evaluating cognitive indices beyond mean neuropsychological scores may provide valuable information when determining the extent of post-concussion cognitive dysfunction.
Apolipoprotein E (APOE) ϵ4 Allele Is Associated with Increased Symptom Reporting Following Sports Concussion
- Victoria C. Merritt, Peter A. Arnett
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- Journal:
- Journal of the International Neuropsychological Society / Volume 22 / Issue 1 / January 2016
- Published online by Cambridge University Press:
- 20 October 2015, pp. 89-94
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Exploring the relationship between genetic factors and outcome following brain injury has received increased attention in recent years. However, few studies have evaluated the influence of genes on specific sequelae of concussion. The purpose of this study was to determine how the ϵ4 allele of the apolipoprotein E (APOE) gene influences symptom expression following sports-related concussion. Participants included 42 collegiate athletes who underwent neuropsychological testing, including completion of the Post-Concussion Symptom Scale (PCSS), within 3 months after sustaining a concussion (73.8% were evaluated within 1 week). Athletes provided buccal samples that were analyzed to determine the make-up of their APOE genotype. Dependent variables included a total symptom score and four symptom clusters derived from the PCSS. Mann-Whitney U tests showed higher scores reported by athletes with the ϵ4 allele compared to those without it on the total symptom score and the physical and cognitive symptom clusters. Furthermore, logistic regression showed that the ϵ4 allele independently predicted those athletes who reported physical and cognitive symptoms following concussion. These findings illustrate that ϵ4+ athletes report greater symptomatology post-concussion than ϵ4- athletes, suggesting that the ϵ4 genotype may confer risk for poorer post-concussion outcome. (JINS, 2016, 22, 89–94)