Traumatic Brain Injury Group Research Articles

Deciphering Proteomic Expression in Inflammatory Disorders: A Mass Spectrometry Exploration Comparing Infectious, Noninfectious, and Traumatic Brain Injuries in Human Cerebrospinal Fluid.

The central nervous system (CNS) evokes a complex inflammatory response to injury. Inflammatory cascades are present in traumatic, infectious, and noninfectious disorders affecting the brain. It contains a mixture of pro- and anti-inflammatory reactions involving well-known proteins, but also numerous proteins less explored in these processes. The aim of this study was to explore the distinct inflammatory response in traumatic brain injury (TBI) compared with other CNS injuries by utilization of mass-spectrometry. In total, 56 patients had their cerebrospinal fluid (CSF) analyzed with the use of mass-spectrometry. Among these, CSF was collected via an external ventricular drain (EVD) from n = 21 patients with acute TBI. The resulting protein findings were then compared with CSF obtained by lumbar puncture from n = 14 patients with noninfectious CNS disorders comprising relapsing-remitting multiple sclerosis, anti-N-methyl-d-aspartate-receptor encephalitis, acute disseminated encephalomyelitis, and n = 14 patients with progressive multifocal leukoencephalopathy, herpes simplex encephalitis, and other types of viral meningitis. We also utilized n = 7 healthy controls (HCs). In the comparison between TBI and noninfectious inflammatory CNS disorders, concentrations of 55 proteins significantly differed between the groups. Among them, 23 and 32 proteins were up- and downregulated, respectively, in the TBI group. No proteins were uniquely identified in either group. In the comparison of TBI and HC, 51 proteins were significantly different, with 24 and 27 proteins being up- and downregulated, respectively, in TBI. Two proteins (fibrinogen gamma chain and transketolase) were uniquely identified in all samples of the TBI group. Also in the last comparison, TBI versus infectious inflammatory CNS disorders, 51 proteins differed between the two groups, with 19 and 32 proteins being up- and downregulated, respectively, in TBI, and no unique proteins being identified. Due to large discrepancies between the groups compared, the following proteins were selected for further deeper analysis among those being differentially regulated: APOE, CFB, CHGA, CHI3L1, C3, FCGBP, FGA, GSN, IGFBP7, LRG1, SERPINA3, SOD3, and TTR. We found distinct proteomic profiles in the CSF of TBI patients compared with HC and different disease controls, indicating a specific interplay between inflammatory factors, metabolic response, and cell integrity. In relation to primarily infectious or inflammatory disorders, unique inflammatory pathways seem to be engaged, and could potentially serve as future treatment targets.

Traumatic brain injury-induced peripheral damage: The dynamics of the inflammatory and autophagy pathway from acute to chronic stages.

Traumatic brain injury (TBI) is one of the major causes of death and disability worldwide, and brings a huge burden on the quality of life of patients with TBI and the country's healthcare system. Peripheral organs, especially the kidney, and liver, may be affected by the onset of molecular responses following brain tissue damage. While secondary injury responses post TBI has been well studied in the brain, the effect/consequences of these responses in the peripheral organs have not yet been fully elucidated. Thus, our study aimed to investigate the immunoreactivity of these responses, particularly via proinflammatory cytokines and autophagy markers in the kidney and liver post-acute and chronic TBI. Mild TBI (mTBI) and repetitive mTBI (r-mTBI) were induced in male and female 2-month-old Balb/c mice via the Marmarou weight-drop model. Liver and kidney tissues were sampled at 24 hours (acute) and 30 days (chronic) post TBI and subjected to histopathological and immunoreactivity analysis. Interleukin (IL)-6 levels were significantly increased in the male liver and kidney tissues in both TBI groups compared to the control group but were seen to be decreased in the female r-mTBI chronic liver and r-mTBI acute kidney. Tumor necrosis factor a (TNF-a) levels were found to increase only in the female r-mTBI chronic kidney tissue and mTBI chronic liver tissue. IL-1b levels were increased in the male and female r-mTBI liver tissues but decreased in the female mTBI kidney tissue. Inducible nitric oxide synthase (iNOS) levels were found to be significantly increased in the female mTBI acute and r-mTBI chronic kidney tissue and mTBI liver tissue, but decreased in the r-mTBI acute kidney and r-mTBI liver tissues. Beclin-1 levels were increased in male mTBI chronic and r-mTBI acute liver tissue but decreased in the r-mTBI chronic group. LC3A/B and P62/SQSTM1 levels were significantly increased in the female mTBI chronic and male r-mTBI chronic liver tissues but decreased in the male r-mTBI and female r-mTBI acute kidney tissues. Significant histopathological changes were also observed in the liver and kidney tissue which were dependent on the TBI severity, gender, and time post TBI. The results showed that TBI may elicit peripheral molecular responses, particularly in terms of alteration in the levels of inflammatory cytokines and autophagy markers, which were gender- and time-dependent. This suggests that TBI may have a significant role in the cellular damage of the kidney and liver in both the acute and chronic phases post TBI, thus ensuring that the effects of TBI may not be confined to the brain.

Resveratrol showed anti-inflammatory effects on hippocampus via suppressing NFκB.

Traumatic brain injury (TBI) is the damage to the brain caused by external blow or jolt to the head or body. TBI secondarily induces cell damage in the hippocampus. This study aimed to investigate effects of resveratrol treatment histological examination and nuclear factor kappa B (NFκB) expression in hippocampus after TBI. Twenty-four rats were assigned to three groups: sham, TBI and TBI+Resveratol. TBI was conducted by dropping a 50-g weight from a 1-meter height from a tube to the head of animals. 20 mg/kg resveratrol was orally administered to rats after TBI. Blood was collected to measure malondialdehyde (MDA) and glutathione (GSH) contents. Cerebral tissues were processed for histopathology and furtherly for immunohistochemical analysis. MDA content was significantly increased and GSH value were significantly decreased in TBI group compared to sham group. Resveratrol treatment significantly improved biochemical scores in TBI+Resveratrol group. Normal histological appearance was observed in hippocampal sections of sham group. In TBI group, neurons in hippocampus were degenerated. Their nuclei were pyknotic. Other neurons and supportive neuroglial cells in hippocampal proper and dentate gyrus were also disrupted. Hippocampal proper integrity was lost with vascular dilatation. NFκB was upregulated in hippocampal neurons of TBI group. Resveratrol treatment alleviated pathologies and downregulated NFκB expression in hippocampus. TBI caused adverse alterations in free radicals' balance system and histological structures of hippocampus. Resveratrol with its antioxidant and anti-inflammatory effects reduced the damage caused by TBI.

Tau Imaging in Late Traumatic Brain Injury: A [18F]MK-6240 Positron Emission Tomography Study.

Epidemiological studies have identified prior traumatic brain injury (TBI) as a risk factor for developing Alzheimer's disease (AD). Neurofibrillary tangles (NFTs) are common to AD and chronic traumatic encephalopathy following repetitive mild TBI. However, it is unclear if a single TBI is sufficient to cause accumulation of NFTs. We performed a [18F]MK-6240 positron emission tomography (PET) imaging study to assess NFTs in patients who had sustained a single TBI at least 2 years prior to study inclusion. Fourteen TBI patients (49 ± 20 years; 5 M/9 F; 8 moderate-severe, 1 mild-probable, 5 symptomatic-possible TBI) and 40 demographically similar controls (57 ± 19 years; 19 M/21 F) underwent simultaneous [18F]MK-6240 PET and magnetic resonance imaging (MRI) as well as neuropsychological assessment including the Cambridge Neuropsychological Test Automated Battery (CANTAB). A region-based voxelwise partial volume correction was applied, using parcels obtained by FreeSurfer v6.0, and standardized uptake value ratios (SUVR) were calculated relative to the cerebellar gray matter. Group differences were assessed on both a voxel- and a volume-of-interest-based level and correlations of [18F]MK-6240 SUVR with time since injury as well as with clinical outcomes were calculated. Visual assessment of TBI images did not show global or focal increases in tracer uptake in any subject. On a group level, [18F]MK-6240 SUVR was not significantly different in patients versus controls or between subgroups of moderate-severe TBI versus less severe TBI. Within the TBI group, One Touch Stockings problem solving and spatial working memory (executive function), reaction time (attention), and Mini-Mental State Examination (MMSE) (global cognition) were associated with [18F]MK-6240 SUVR. We found no group-based increase of [18F]MK-6240 brain uptake in patients scanned at least 2 years after a single TBI compared with healthy volunteers, which suggests that no NFTs are building up in the first years after a single TBI. Nonetheless, correlations with cognitive outcomes were found that warrant further investigation.

Deferoxamine Induces Autophagy Following Traumatic Brain Injury via TREM2 on Microglia.

Previous studies have indicated that iron disorder, inflammation, and autophagy play an important role in traumatic brain injury (TBI). The triggering receptor expressed on myeloid cells 2 (TREM2), an immunoglobulin superfamily transmembrane receptor, is involved in inflammation. However, the role of TREM2 in modulating the microglia response in TBI has been rarely investigated. The present study aimed to investigate if the iron chelator deferoxamine (DFO) could ameliorate TBI through autophagy mediated by the TREM2. TBI was developed by the controlled cortical impact (CCI) mouse model and stretching of individual primary cortical microglia taken from the tissue of the rat brain. DFO was intraperitoneally used for intervention. Western blotting assay, qRT-PCR, TUNEL staining, immunofluorescence staining, confocal microscopy analysis, transmission electron microscopy, H&E staining, brain water content measurement, and the neurobehavioral assessments were performed. TREM2 expression was up-regulated in cortex of TBI mice model and in microglia stretching model, which was attenuated by DFO. After the mice were subjected to CCI, DFO treatment significantly up-regulated the protein levels of autophagy compared with the TBI group at 3days and caused an increase of autophagic vacuoles. Treatment with DFO reduced TBI-induced cell apoptosis, cerebral edema, neuroinflammation, and motor function impairment in mice, at least partly via the mTOR signaling pathway that facilitates the TREM2 activity. The results indicated that the maintenance of iron homeostasis by DFO plays neuroprotection by modulating the inflammatory response to TBI through TREM2-mediated autophagy. This study suggested that TREM2-mediated autophagy might be a potential target for therapeutic intervention in TBI.

Subcortical functional connectivity and its association with walking performance following deployment related mild TBI.

The relation between traumatic brain injury (TBI), its acute and chronic symptoms, and the potential for remote neurodegenerative disease is a priority for military research. Structural and functional connectivity (FC) of the basal ganglia, involved in motor tasks such as walking, are altered in some samples of Service Members and Veterans with TBI, but any behavioral implications are unclear and could further depend on the context in which the TBI occurred. In this study, FC from caudate and pallidum seeds was measured in Service Members and Veterans with a history of mild TBI that occurred during combat deployment, Service Members and Veterans whose mild TBI occurred outside of deployment, and Service Members and Veterans who had no lifetime history of TBI. FC patterns differed for the two contextual types of mild TBI. Service Members and Veterans with deployment-related mild TBI demonstrated increased FC between the right caudate and lateral occipital regions relative to both the non-deployment mild TBI and TBI-negative groups. When evaluating the association between FC from the caudate and gait, the non-deployment mild TBI group showed a significant positive relationship between walking time and FC with the frontal pole, implicated in navigational planning, whereas the deployment-related mild TBI group trended towards a greater negative association between walking time and FC within the occipital lobes, associated with visuo-spatial processing during navigation. These findings have implications for elucidating subtle motor disruption in Service Members and Veterans with deployment-related mild TBI. Possible implications for future walking performance are discussed.

Diffusion basis spectrum imaging detects subclinical traumatic optic neuropathy in a closed-head impact mouse model of traumatic brain injury.

Traumatic optic neuropathy (TON) is the optic nerve injury secondary to brain trauma leading to visual impairment and vision loss. Current clinical visual function assessments often fail to detect TON due to slow disease progression and clinically silent lesions resulting in potentially delayed or missed treatment in patients with traumatic brain injury (TBI). Diffusion basis spectrum imaging (DBSI) is a novel imaging modality that can potentially fill this diagnostic gap. Twenty-two, 16-week-old, male mice were equally divided into a sham or TBI (induced by moderate Closed-Head Impact Model of Engineered Rotational Acceleration device) group. Briefly, mice were anesthetized with isoflurane (5% for 2.5 min followed by 2.5% maintenance during injury induction), had a helmet placed over the head, and were placed in a holder prior to a 2.1-joule impact. Serial visual acuity (VA) assessments, using the Virtual Optometry System, and DBSI scans were performed in both groups of mice. Immunohistochemistry (IHC) and histological analysis of optic nerves was also performed after in vivo MRI. VA of the TBI mice showed unilateral or bilateral impairment. DBSI of the optic nerves exhibited bilateral involvement. IHC results of the optic nerves revealed axonal loss, myelin injury, axonal injury, and increased cellularity in the optic nerves of the TBI mice. Increased DBSI axon volume, decreased DBSI λ||, and elevated DBSI restricted fraction correlated with decreased SMI-312, decreased SMI-31, and increased DAPI density, respectively, suggesting that DBSI can detect coexisting pathologies in the optic nerves of TBI mice. DBSI provides an imaging modality capable of detecting subclinical changes of indirect TON in TBI mice.

Action control and selection in social disinhibition following severe TBI: a pavlovian-to-instrumental transfer and outcome devaluation study

ABSTRACT Introduction Social disinhibition is a significant sequela of severe traumatic brain injury (TBI). Some research suggests that it could reflect a deficiency in goal-directed behavior. The current study aimed to test whether these inappropriate behaviors tend to be deficient in goal-directed control, that is, triggered more by environmental stimuli than by the known consequences of their actions. Method We used a between-group design with 25 adult participants with severe TBI, and 27 control participants. Social disinhibition was measured using Frontal Systems Behavior Scale and Social Disinhibition Interview. Changes in reward-related goal-directed behavior were evaluated using a computer-based task in which we assessed the influence of cues predicting reward and of reward devaluation on choice performance. Results We found no difference in the levels of social disinhibition between the TBI and control groups and, using mixed two-way ANCOVAs, no overall effect of the stimuli or outcome devaluation. However, after combing these groups and splitting them based on their disinhibition levels, a significant interaction between group (High vs Low disinhibition) and reward type (Valued vs Devalued) in sensitivity to outcome devaluation test (F = 5.99, p = .01, ηp2 = .13) appeared. Comparing with the baseline rate of responding, the Low disinhibition group decreased their responding to devalued and increased their responding to still-valued outcomes. In contrast, the High disinhibition group showed the opposite pattern of choice performance. Conclusions It appears that people with clinical levels of social disinhibition are both prone to outcome-response priming effects and insensitive to changes in the value of the consequences of their actions, that is, despite evidence they were aware of the reduction in the value of their actions’s outcomes, people with high-level disinhibition kept performing those actions. This pattern has the hallmarks of a habit suggesting their disinhibition reflects a loss of executive control.

Traumatic brain injury extending to the striatum alters autonomic thermoregulation and hypothalamic monoamines in recovering rats.

The brain cortex is the structure that is typically injured in traumatic brain injury (TBI) and is anatomically connected with other brain regions, including the striatum and hypothalamus, which are associated in part with motor function and the regulation of body temperature, respectively. We investigated whether a TBI extending to the striatum could affect peripheral and core temperatures as an indicator of autonomic thermoregulatory function. Moreover, it is unknown whether thermal modulation is accompanied by hypothalamic and cortical monoamine changes in rats with motor function recovery. The animals were allocated into three groups: the sham group (sham), a TBI group with a cortical contusion alone (TBI alone), and a TBI group with an injury extending to the dorsal striatum (TBI + striatal injury). Body temperature and motor deficits were evaluated for 20 days post-injury. On the 3rd and 20th days, rats were euthanized to measure the serotonin (5-HT), noradrenaline (NA), and dopamine (DA) levels using high-performance liquid chromatography (HPLC). We observed that TBI with an injury extending to the dorsal striatum increased core and peripheral temperatures. These changes were accompanied by a sustained motor deficit lasting for 14 days. Furthermore, there were notable increases in NA and 5-HT levels in the brain cortex and hypothalamus both 3 and 20 days after injury. In contrast, rats with TBI alone showed no changes in peripheral temperatures and achieved motor function recovery by the 7th day post-injury. In conclusion, our results suggest that TBI with an injury extending to the dorsal striatum elevates both core and peripheral temperatures, causing a delay in functional recovery and increasing hypothalamic monoamine levels. The aftereffects can be attributed to the injury site and changes to the autonomic thermoregulatory functions.

Effects of Intrathecal Ketamine on Cerebrospinal Fluid Levels of Brain-Derived Neurotrophic Factor and Mechanical Allodynia in a Rat Model of Mild Traumatic Brain Injury.

BACKGROUND Ketamine, a compelling candidate for neuropathic pain management, has attracted interest for its potential to elevate brain-derived neurotrophic factor (BDNF) levels. We aimed to assess the effects of intrathecally administered ketamine on the cerebrospinal fluid (CSF) levels of BDNF(c-BDNF) and allodynia in a rat model of traumatic brain injury (TBI). MATERIAL AND METHODS Forty-five rats were divided into 3 groups: sham operation (Group S), untreated TBI (Group T), and ketamine-treated TBI (Group K), with 15 rats in each group. Rats were anesthetized, and their skulls were secured in a stereotactic frame before undergoing craniotomy. A controlled cortical impact (CCI) was induced, followed by injection of ketamine (3.41 µg/g) into the CSF in Group K. In Group T, no drug was injected after CCI delivery. On postoperative days (POD) 1, 7, and 14, the 50% mechanical withdrawal threshold (50% MWT) and c-BDNF levels were assessed. RESULTS Groups T and K exhibited a significantly lower 50% MWT than Group S on POD 1(6.6 [5.7, 8.7] g, 10.0 [6.8, 11.6] g, and 18.7 [11.6, 18.7] g, respectively; P<0.001). The c-BDNF levels in Group K were significantly higher than those in Groups S and T on POD 1 (18.9 [16.1, 23.0] pg/ml, 7.3 [6.0, 8.8] pg/ml, and 11.0 [10.6, 12.3] pg/ml, respectively; P=0.006). CONCLUSIONS Intrathecal ketamine administration did not exhibit anti-allodynic effects following mild TBI. c-BDNF level is a promising potential indicator for predicting the expression of allodynia after mild TBI.

Neuropsychiatric symptoms after moderate-to-severe traumatic brain injury in Vietnam: Assessment, prevalence, and impact on caregivers.

Neuropsychiatric symptoms (NPSs) after moderate-to-severe traumatic brain injury (TBI) have been well documented in WEIRD (Western, educated, industrialized, rich, and democratic) populations. In non-WEIRD populations, such as Vietnam, however, patients with TBI clinically remain uninvestigated with potential neuropsychiatric disorders, limiting on-time critical interventions. This study aims to (1) adapt the Vietnamese Neuropsychiatric Inventory (V-NPI), (2) examine NPSs after moderate-to-severe TBI and (3) evaluate their impact on caregiver burden and well-being in Vietnam. Caregivers of seventy-five patients with TBI completed the V-NPI, and other behavior, mood, and caregiver burden scales. Our findings demonstrated good internal consistency, convergent validity, and structural validity of the V-NPI. Caregivers reported that 78.7% of patients with TBI had at least three symptoms and 16.0% had more than seven. Behavioral and mood symptoms were more prevalent (ranging from 44.00% to 82.67% and from 46.67% to 66.67%, respectively) and severe in the TBI group. Importantly, NPSs in patients with TBI uniquely predicted 55.95% and 33.98% of caregiver burden and psychological well-being, respectively. This study reveals the first evidence for the presence and severity of NPSs after TBI in Vietnam, highlighting an urgent need for greater awareness and clinical assessment of these symptoms in clinical practice. The adapted V-NPI can serve as a useful tool to facilitate such assessments and interventions. In addition, given the significant impact of NPS on caregiver burden and well-being, psychosocial support for caregivers should be established.

Evaluating the effects of brain injury, disease and tasks on cognitive fatigue

Because cognitive fatigue (CF) is common and debilitating following brain injury or disease we investigated the relationships among CF, behavioral performance, and cerebral activation within and across populations by combining the data from two cross-sectional studies. Individuals with multiple sclerosis (MS) were included to model CF resulting from neurological disease; individuals who had sustained a traumatic brain injury (TBI) were included to model CF resulting from neurological insult; both groups were compared with a control group (Controls). CF was induced while neuroimaging data was acquired using two different tasks. CF significantly differed between the groups, with the clinical groups reporting more CF than Controls—a difference that was statistically significant for the TBI group and trended towards significance for the MS group. The accrual of CF did not differ across the three groups; and CF ratings were consistent across tasks. Increasing CF was associated with longer response time for all groups. The brain activation in the caudate nucleus and the thalamus was consistently correlated with CF in all three groups, while more dorsally in the caudate, activation differed across the groups. These results suggest the caudate and thalamus to be central to CF while more dorsal aspects of the caudate may be sensitive to damage associated with particular types of insult.

Clinical complications after a traumatic brain injury and its relation with brain biomarkers

We aimed to find out which are the most frequent complications for patients who suffer a traumatic brain injury (TBI) and its relation with brain biomarker levels. We conducted a hospital cohort study with patients who attended the Hospital Emergency Department between 1 June 2018 and 31 December 2020. Different variables were collected such as biomarkers levels after 6 h and 12 h of TBI (S100, NSE, UCHL1 and GFAP), clinical and sociodemographic variables, complementary tests, and complications 48 h and 7 days after TBI. Qualitative variables were analysed with Pearson’s chi-square test, and quantitative variables with the Mann–Whitney U test. A multivariate logistic regression model for the existence of complications one week after discharge was performed to assess the discriminatory capacity of the clinical variables. A total of 51 controls and 540 patients were included in this study. In the TBI group, the mean age was 83 years, and 53.9% of the patients were male. Complications at seven days were associated with the severity of TBI (p < 0.05) and the number of platelets (p = 0.016). All biomarkers except GFAP showed significant differences in their distribution of values according to gender, with significantly higher values of the three biomarkers for women with respect to men. Patients with complications presented significantly higher S100 values (p < 0.05). The patient’s baseline status, the severity of the TBI and the S100 levels can be very important elements in determining whether a patient may develop complications in the few hours after TBI.

Behavioral deficits after mild traumatic brain injury by fluid percussion in rats

Mild traumatic brain injury (TBI) can lead to various disorders, encompassing cognitive and psychiatric complications. While pre-clinical studies have long investigated behavioral alterations, the fluid percussion injury (FPI) model still lacks a comprehensive behavioral battery that includes psychiatric-like disorders. To address this gap, we conducted multiple behavioral tasks over two months in adult male Wistar rats, focusing on mild FPI. Statistical analyses revealed that both naive and sham animals exhibited an increase in sweet liquid consumption over time. In contrast, the TBI group did not show any temporal changes, although mild FPI did induce a statistically significant decrease in sucrose consumption compared to control groups during the chronic phase. Additionally, social interaction tasks indicated reduced contact time in TBI animals. The elevated plus maze task demonstrated an increase in open-arm exploration following fluid percussion. Nonetheless, no significant differences were observed in the acute and chronic phases for the forced swim and light–dark box tasks. Evaluation of three distinct memory tasks in the chronic phase revealed that mild FPI led to long-term memory deficits, as assessed by the object recognition task, while the surgical procedure itself resulted in short-term spatial memory deficits, as evaluated by the Y-maze task. Conversely, working memory remained unaffected in the water maze task. Collectively, these findings provide a nuanced characterization of behavioral deficits induced by mild FPI.

Self-Reported Symptoms of Vertigo and Imbalance Are Prevalent Among Adults With Chronic Moderate-Severe Traumatic Brain Injury: A Preliminary Analysis.

Dizziness and imbalance are common symptoms during the acute phase of traumatic brain injury (TBI). However, there is evidence to suggest that these symptoms persist into the chronic phase of injury. Few prospective studies have examined the frequency and type of dizziness and imbalance in adults with chronic moderate-severe TBI. The aim of this preliminary analysis was to investigate the prevalence of these symptoms in adults with chronic moderate-severe TBI. Twenty-four adults with chronic moderate-severe TBI and a group of 19 age-, sex-, and education-matched noninjured comparison participants were recruited. Self-reported dizziness and imbalance were measured using a modified version of a standard case history form. Significant associations between group (TBI group or noninjured comparison [NC] participants) and self-reports of dizziness, imbalance, and related symptoms (endorsed "yes" or "no") were explored. The TBI group most reported lightheadedness (75%), vertigo (38%), and imbalance and/or falling (46%). The most common related symptom reported by the TBI group was headache (63%) and nausea (46%). Significant associations revealed that the TBI group responded "yes" in higher percentages than the NC group across all categories (dizziness, imbalance, and related symptoms). There were no statistically significant relationships among dizziness, imbalance, or headache symptoms within the TBI group. These preliminary findings suggest that dizziness and imbalance are prevalent in adults with chronic moderate-severe TBI. Persistent vertiginous symptoms may point to an underlying vestibular impairment. However, further research is needed to characterize vestibular function in chronic moderate-severe TBI.

12 Traumatic Brain Injury as a Moderator on Apolipoprotein-E Risk Associated with Earlier Onset of Alzheimer's Disease

Objective:Prior studies have determined the Apolipoprotein-E (ApoE) ε4 allele presents a greater risk for developing Alzheimer's disease and for earlier onset of cognitive decline compared to individuals without the gene. Research has also recognized that traumatic brain injuries (TBIs) with loss of consciousness increase the risk for earlier development of the disease. This study sought to determine the moderating factor of TBI history on ApoE-ε4 risk associated with earlier Alzheimer's disease onset.Participants and Methods:Participants included 9,585 individuals with autopsy confirmed Alzheimer's disease pathology, that had available ApoE genotype data, TBI data, and clinician determined age of cognitive decline, representing disease onset. A 2x3 factorial ANOVA was conducted to compare the main effects of ApoE-ε4 status and TBI history and the interaction effect between the two on disease onset. The analyses used three ApoE-ε4 groups and two TBI groups. The groups included: (1) no ApoE-ε4 allele; (2) one ApoE-ε4 allele; (3) two ApoE-ε4 alleles; (4) no TBI history, (5) positive TBI history.Results:Results indicated a significant interaction effect between ApoE-ε4 status and TBI history. Secondary analyses determined the driving force behind the interaction was the effect of ApoE-ε4, which had a significant impact on the age of onset in both TBI groups, while TBI history only significantly impacted onset in individuals without an ApoE-ε4 allele.Conclusions:Contrary to prior research, these findings did not indicate TBI was significant in determining earlier onset. However, it is important to consider the large variability within the TBI group from the lack of differentiation between mild, moderate, and severe TBIs. Overall, these findings underline the greater risk and stronger impact that ApoE-ε4 poses for Alzheimer's disease onset compared to TBI. The results of this study emphasize the importance of evaluating ApoE-ε4 status for determining risk of earlier onset AD. Clinicians can better determine risk by considering patients' ApoE-ε4 status alongside TBI history.

11 The Moderating Effect of Depression on Workload Perception in Traumatic Brain Injury

Objective:Individuals who have experienced traumatic brain injury (TBI) are at an elevated risk for worsened physical and psychological outcomes. Increased rates of anxiety and depression, along with cognitive issues, are common post-TBI. While there is some evidence that anxiety and depression may affect objective cognitive performance, less is known about their effect on other factors that are associated with the individual’s capacity to complete the task, such as perceived workload of the cognitive task. Workload represents an individual’s perception of task difficulty and serves as a proxy for the magnitude of mental demands a given task places on an individual. Preliminary findings in the literature suggest that individuals with TBI commonly report greater workload when completing cognitive tasks compared to neurotypical peers, but the influence of anxiety and depression on survivors’ workload remains unclear. Considering the elevated rates of psychological and cognitive problems in individuals with TBI, the present study examined the moderating role of anxiety and depression on TBI survivor workload perception of a stress-inducing working memory task.Participants and Methods:Ten participants with moderate to severe TBI and eight neurologically healthy controls performed the Paced Auditory Serial Addition Task (PASAT). After completing the PASAT, participants reported their subjective workload using the NASA task load index (NASA-TLX). Participants also completed measures of psychological functioning, including the Chicago Multiscale Depression Inventory (CMDI) and the State-Trait Anxiety Inventory (STAI). Relationships between workload and depression and trait anxiety were examined using linear regression.Results:Linear regression was employed for both the TBI and the healthy control groups to assess the influence of trait anxiety and depression on perceived workload. There was no significant difference between the TBI and HC NASA perceived workload scores. Within the TBI group, there was a significant anxiety by depression interaction (b = -.015, p &lt; .001). Simple slopes analyses revealed that for TBI participants reporting low depression, perceived workload increased with increased anxiety (b = .093, p &lt; .001). For TBI participants reporting high depression, perceived workload decreased as anxiety increased (b = -.38, p = .03). While there was also significant anxiety by depression interaction in the healthy control group (b = .033, p = .04), simple slopes analyses revealed that there were no significant associations for healthy controls.Conclusions:These results demonstrate that in TBI, level of depression moderates the relationship between anxiety and workload perception. The pattern observed in the TBI group was unique from controls. The present findings suggest that post-TBI, higher depression may temper the influence of anxiety on stressful cognitive task performance and workload rating. The tempering effect of high depression in TBI may represent a biased reporting style or impaired assessment of task difficulty, which may ultimately affect the individual’s capacity to accomplish a task well.

56 TBI Severity Moderates the Association between Subjective and Objective Attention in Older Veterans

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&lt;.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.

History of traumatic brain injury does not alter course of neurocognitive decline in older adults with and without cognitive impairment.

Traumatic brain injury (TBI) history is associated with dementia risk, but it is unclear whether TBI history significantly hastens neurocognitive decline in older adults. Data were derived from the National Alzheimer's Coordinating Center (NACC) data set. Participants with a history of TBI (TBI +; n = 1,467) were matched to individuals without a history of TBI (TBI-; n = 1,467) based on age (50-97, M = 71.61, SD = 8.40), sex, education, race, ethnicity, cognitive diagnosis, functional decline, number of Apolipoprotein ε4 (APOE ε4) alleles, and number of annual visits (3-6). Mixed linear models were used to assess longitudinal neuropsychological test composite scores of executive functioning/attention/speed, language, and memory in TBI + and TBI- participants. Interactions between TBI and demographics, APOE ε4 status, and cognitive diagnosis were also examined. Longitudinal neuropsychological functioning did not differ between TBI groups (p's > .001). There was a significant three-way interaction (age, TBI history, time) in language (F[20, 5750.1] = 3.133, p < .001) and memory performance (F[20, 6580.8] = 3.386, p < .001), but post hoc analyses revealed TBI history was not driving this relationship (all p's > .096). No significant interactions were observed between TBI history and sex, education, race/ethnicity, number of APOE ε4 alleles, or cognitive diagnosis (p's > .001). Findings suggest TBI history, regardless of demographic factors, APOE ε4 status, or cognitive diagnosis, does not alter the course of neurocognitive functioning later-in-life in older adults with or without cognitive impairment. Future clinicopathological longitudinal studies that well-characterize head injuries and the associated clinical course are needed to help clarify the mechanism in which TBI may increase dementia risk. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

4 Traumatic Brain Injury Does Not Alter the Course of Neurocognitive Functioning Later in Life

Objective:History of traumatic brain injury (TBI) is associated with increased risk of dementia, but few studies have evaluated whether TBI history alters the course of neurocognitive decline, and existing literature on this topic is limited to short follow-up and smaller samples. The primary aim of this study was to evaluate whether a history of TBI (TBI+) influences neurocognitive decline later-in-life among older adults with or without cognitive impairment [i.e., normally aging, Mild Cognitive Impairment (MCI), or dementia].Participants and Methods:Participants included individuals from the National Alzheimer’s Coordinating Center (NACC) who were at least 50 years old and with 3 to 6 visits (M number of visits = 4.43). Participants with any self-reported history of TBI (n = 1,467) were matched 1:1 to individuals with no reported history of TBI (TBI-) from a sample of approximately 45,000 participants using case-control matching based on age (+/- 2 years), sex, education, race, ethnicity, cognitive diagnosis [cognitively normal (CN), MCI, or all-cause dementia], etiology of cognitive impairment, functional decline (Clinical Dementia Rating Scale, CDR), number of Apolipoprotein E4 (APOE ε4) alleles, and number of annual visits (3 to 6). Mixed linear models were used to assess longitudinal neuropsychological test composites (using NACC normative data) of executive functioning/attention/speed (EFAS), language, and memory in TBI+ and TBI- participants. Interactions between TBI and demographics, APOE ε4 status, and cognitive diagnosis were also examined.Results:Following matching procedures, TBI+ (n=1467) and TBI- (n=1467) groups were nearly identical in age (TBI+ M = 71.59, SD = 8.49; TBI- M = 71.63, SD = 8.44), education (TBI+ M = 16.12, SD = 2.59; TBI- M = 16.10, SD = 2.52), sex (both 55% male), race (both 90% White), ethnicity (both 98% non-Hispanic), APOE ε4 alleles (both 0 = 62%, 1 = 33%, 2 = 5%), baseline cognitive diagnoses (both CN = 60%, MCI = 18%, dementia = 12%), and global CDR (TBI+ M = 0.30, SD = 0.38, TBI- M = 0.30, SD = 0.38). At baseline, groups had similar Z-scores of in EFAS (TBI+ Mefas = -0.02, SD = 1.21; TBI- Mefas = -0.04, SD = 1.27), language (TBI+ MLanguage = -0.48, SD = 0.98; TBI- MLanguage = -0.55, SD = 1.05), and memory (TBI+ MMemory = -0.45, SD = 1.28; TBI- MMemory = -0.45, SD =1.28). The course of change in neuropsychological functioning worsened longitudinally, but did not differ between TBI groups (p’s &gt; .110). There were no significant interactions between TBI history and age, sex, education, race/ethnicity, number of APOE ε4 status, or cognitive diagnosis (all p’s &gt; .027).Conclusions:In this matched case-control design, our findings suggest that a history of TBI, regardless of demographic factors, APOE ε4 status, and cognitive diagnosis, does not significantly alter the course of neurocognitive functioning later-in-life in older adults with and without cognitive impairment. Future clinicopathological longitudinal studies with well characterized TBI histories and the associated clinical course are needed to help clarify the mechanism by which TBI may increase dementia risk for some individuals, without affecting course of decline.