P1‐311: Chronic traumatic encephalopathy (CTE) in blast‐exposed U.S. military veterans and a new blast neurotrauma mouse model

Goldstein, Lee E.; Fisher, Andrew M.; Tagge, Chad A.; Zhang, Xiaolei; Velı́šek, Libor; Sullivan, John A.; Upreti, Chirag; Kracht, Johnathan; Ericsson, Maria; Wojnarowicz, Mark; Goletiani, Cezar; Maglakelidze, Giorgi; Casey, Noel; Moncaster, Juliet A.; Minaeva, Olga; Cormier, Kerry; Kubilus, Caroline A.; Moir, Robert D.; Nowinski, Christopher J.; Stern, Robert; Cantu, Robert C.; Geiling, James; Blusztajn, Jan Krzysztof; Wolozin, Benjamin; Ikezu, Tsuneya; Budson, Andrew E.; Saman, Sudad; Hall, Garth F.; Chargin, David; Sharon, André; Moss, William C.; Kowall, Neil W.; Cleveland, Robin O.; Tanzi, Rudolph E.; Stanton, Patric K.; McKee, Ann C.

doi:10.1016/j.jalz.2012.05.592

Cited by 10 publications

(6 citation statements)

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“…Chronic repetitive neurotrauma has been associated with increased pTau accumulation in the brain, at least in some cases (79)(80)(81)(82), and pTau deposits are considered a major diagnostic feature of CTE (7,8). However, much less is known about the effect of a single or a few mild concussive events.…”

Section: Discussionmentioning

confidence: 99%

The Delayed Neuropathological Consequences of Traumatic Brain Injury in a Community-Based Sample

et al. 2021

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The late neuropathological effects of traumatic brain injury have yet to be fully elucidated, particularly with respect to community-based cohorts. To contribute to this critical gap in knowledge, we designed a multimodal neuropathological study, integrating traditional and quantitative approaches to detect pathologic changes in 532 consecutive brain autopsies from participants in the Adult Changes in Thought (ACT) study. Diagnostic evaluation including assessment for chronic traumatic encephalopathy (CTE) and quantitative immunoassay-based methods were deployed to examine levels of pathological (hyperphosphorylated) tau (pTau) and amyloid (A) β in brains from ACT participants with (n = 107) and without (n = 425) history of remote TBI with loss of consciousness (w/LOC). Further neuropathological assessments included immunohistochemistry for α-synuclein and phospho-TDP-43 pathology and astro- (GFAP) and micro- (Iba1) gliosis, mass spectrometry analysis of free radical injury, and gene expression evaluation (RNA sequencing) in a smaller sub-cohort of matched samples (49 cases with TBI and 49 non-exposed matched controls). Out of 532 cases, only 3 (0.6%–none with TBI w/LOC history) showed evidence of the neuropathologic signature of chronic traumatic encephalopathy (CTE). Across the entire cohort, the levels of pTau and Aβ showed expected differences for brain region (higher levels in temporal cortex), neuropathological diagnosis (higher in participants with Alzheimer's disease), and APOE genotype (higher in participants with one or more APOE ε4 allele). However, no differences in PHF-tau or Aβ1−42 were identified by Histelide with respect to the history of TBI w/LOC. In a subset of TBI cases with more carefully matched control samples and more extensive analysis, those with TBI w/LOC history had higher levels of hippocampal pTau but no significant differences in Aβ, α-synuclein, pTDP-43, GFAP, Iba1, or free radical injury. RNA-sequencing also did not reveal significant gene expression associated with any measure of TBI exposure. Combined, these findings suggest long term neuropathological changes associated with TBI w/LOC may be subtle, involve non-traditional pathways of neurotoxicity and neurodegeneration, and/or differ from those in autopsy cohorts specifically selected for neurotrauma exposure.

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Section: Discussionmentioning

confidence: 99%

The Delayed Neuropathological Consequences of Traumatic Brain Injury in a Community-Based Sample

et al. 2021

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“…Memory deficits in open detonation experiments persisted for a month (58). The working memory deficits in Barnes maze were resolved when animals were provided with head restraint (26). Most deficits that lasted weeks post injury observed in the Morris Water maze test also involves animals placed at the exit end of the blast tube.…”

Section: Behavioral Deficits In Blast Tbi Cognitive Deficitsmentioning

confidence: 99%

“…Kuriakose et al, indicated that an end plate reflector placed at an optimum distance to the exit of the blast tube can reduce the reflective waveforms and thereby prevent secondary loading (7). Absence of head restraint during the blast exposure also results in tertiary effects of blast leading to increased behavioral deficits (18,26). The blast overpressure waves decays over the length of the blast tube.…”

Section: Overview Of Blast Apparatus In Rodent Modelsmentioning

confidence: 99%

Behavioral Deficits in Animal Models of Blast Traumatic Brain Injury

et al. 2020

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Blast exposure has been identified to be the most common cause for traumatic brain injury (TBI) in soldiers. Over the years, rodent models to mimic blast exposures and the behavioral outcomes observed in veterans have been developed extensively. However, blast tube design and varying experimental parameters lead to inconsistencies in the behavioral outcomes reported across research laboratories. This review aims to curate the behavioral outcomes reported in rodent models of blast TBI using shockwave tubes or open field detonations between the years 2008–2019 and highlight the important experimental parameters that affect behavioral outcome. Further, we discuss the role of various design parameters of the blast tube that can affect the nature of blast exposure experienced by the rodents. Finally, we assess the most common behavioral tests done to measure cognitive, motor, anxiety, auditory, and fear conditioning deficits in blast TBI (bTBI) and discuss the advantages and disadvantages of these tests.

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“…Goldstein et al (41) reported that the mice exposed to a blast did not show deficits in learning and memory in the absence of rotational and/or acceleration-deceleration forces. As described above, our model was free from the effects of acceleration (tertiary mechanism) but showed behavioral alterations under high impulse conditions.…”

Section: Discussionmentioning

confidence: 99%

“…Second, for neuropathology, we focused only on axonal injury, although we previously reported the increased oxidative stress in the cortex, hippocampus and cerebellum in the same model at 7 days post-exposure (17). Although the clinical neuropathology for bTBI is not fully understood, glial scar formation (47) and aberrant protein accumulation (41) have been reported on the basis of results of studies using postmortem brains of bTBI patients in addition to axonal injury. It is not clear how our neuropathological findings (axonal injury) are associated with those outcomes.…”

Section: Discussionmentioning

confidence: 99%

Behavioral and Histopathological Impairments Caused by Topical Exposure of the Rat Brain to Mild-Impulse Laser-Induced Shock Waves: Impulse Dependency

et al. 2021

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Although an enormous number of animal studies on blast-induced traumatic brain injury (bTBI) have been conducted, there still remain many uncertain issues in its neuropathology and mechanisms. This is partially due to the complex and hence difficult experimental environment settings, e.g., to minimize the effects of blast winds (tertiary mechanism) and to separate the effects of brain exposure and torso exposure. Since a laser-induced shock wave (LISW) is free from dynamic pressure and its energy is spatially well confined, the effects of pure shock wave exposure (primary mechanism) solely on the brain can be examined by using an LISW. In this study, we applied a set of four LISWs in the impulse range of 15–71 Pa·s to the rat brain through the intact scalp and skull; the interval between each exposure was ~5 s. For the rats, we conducted locomotor activity, elevated plus maze and forced swimming tests. Axonal injury in the brain was also examined by histological analysis using Bodian silver staining. Only the rats with exposure at higher impulses of 54 and 71 Pa·s showed significantly lower spontaneous movements at 1 and 2 days post-exposure by the locomotor activity test, but after 3 days post-exposure, they had recovered. At 7 days post-exposure, however, these rats (54 and 71 Pa·s) showed significantly higher levels of anxiety-related and depression-like behaviors by the elevated plus maze test and forced swimming test, respectively. To the best of the authors' knowledge, there have been few studies in which a rat model showed both anxiety-related and depression-like behaviors caused by blast or shock wave exposure. At that time point (7 days post-exposure), histological analysis showed significant decreases in axonal density in the cingulum bundle and corpus callosum in impulse-dependent manners; axons in the cingulum bundle were found to be more affected by a shock wave. Correlation analysis showed a statistically significant correlation between the depression like-behavior and axonal density reduction in the cingulum bundle. The results demonstrated the dependence of behavior deficits and axonal injury on the shock wave impulse loaded on the brain.

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P1‐311: Chronic traumatic encephalopathy (CTE) in blast‐exposed U.S. military veterans and a new blast neurotrauma mouse model

Cited by 10 publications

References 0 publications

The Delayed Neuropathological Consequences of Traumatic Brain Injury in a Community-Based Sample

The Delayed Neuropathological Consequences of Traumatic Brain Injury in a Community-Based Sample

Behavioral Deficits in Animal Models of Blast Traumatic Brain Injury

Behavioral and Histopathological Impairments Caused by Topical Exposure of the Rat Brain to Mild-Impulse Laser-Induced Shock Waves: Impulse Dependency

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