Dataset Information

Brain and blood biomarkers of tauopathy and neuronal injury in humans and rats with neurobehavioral syndromes following blast exposure.

ABSTRACT: Traumatic brain injury (TBI) is a risk factor for the later development of neurodegenerative diseases that may have various underlying pathologies. Chronic traumatic encephalopathy (CTE) in particular is associated with repetitive mild TBI (mTBI) and is characterized pathologically by aggregation of hyperphosphorylated tau into neurofibrillary tangles (NFTs). CTE may be suspected when behavior, cognition, and/or memory deteriorate following repetitive mTBI. Exposure to blast overpressure from improvised explosive devices (IEDs) has been implicated as a potential antecedent for CTE amongst Iraq and Afghanistan Warfighters. In this study, we identified biomarker signatures in rats exposed to repetitive low-level blast that develop chronic anxiety-related traits and in human veterans exposed to IED blasts in theater with behavioral, cognitive, and/or memory complaints. Rats exposed to repetitive low-level blasts accumulated abnormal hyperphosphorylated tau in neuronal perikarya and perivascular astroglial processes. Using positron emission tomography (PET) and the [¹⁸F]AV1451 (flortaucipir) tau ligand, we found that five of 10 veterans exhibited excessive retention of [¹⁸F]AV1451 at the white/gray matter junction in frontal, parietal, and temporal brain regions, a typical localization of CTE tauopathy. We also observed elevated levels of neurofilament light (NfL) chain protein in the plasma of veterans displaying excess [¹⁸F]AV1451 retention. These findings suggest an association linking blast injury, tauopathy, and neuronal injury. Further study is required to determine whether clinical, neuroimaging, and/or fluid biomarker signatures can improve the diagnosis of long-term neuropsychiatric sequelae of mTBI.

SUBMITTER: Dickstein DL

PROVIDER: S-EPMC7484380 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Brain and blood biomarkers of tauopathy and neuronal injury in humans and rats with neurobehavioral syndromes following blast exposure.

Dickstein Dara L DL De Gasperi Rita R Gama Sosa Miguel A MA Perez-Garcia Georgina G Short Jennifer A JA Sosa Heidi H Perez Gissel M GM Tschiffely Anna E AE Dams-O'Connor Kristen K Pullman Mariel Y MY Knesaurek Karin K Knutsen Andrew A Pham Dzung L DL Soleimani Lale L Jordan Barry D BD Gordon Wayne A WA Delman Bradley N BN Shumyatsky Gleb G Shahim Pashtun-Poh PP DeKosky Steven T ST Stone James R JR Peskind Elaine E Blennow Kaj K Zetterberg Henrik H Chance Steven A SA Torso Mario M Kostakoglu Lale L Sano Mary M Hof Patrick R PR Ahlers Stephen T ST Gandy Sam S Elder Gregory A GA

Molecular psychiatry 20200225 10

Traumatic brain injury (TBI) is a risk factor for the later development of neurodegenerative diseases that may have various underlying pathologies. Chronic traumatic encephalopathy (CTE) in particular is associated with repetitive mild TBI (mTBI) and is characterized pathologically by aggregation of hyperphosphorylated tau into neurofibrillary tangles (NFTs). CTE may be suspected when behavior, cognition, and/or memory deteriorate following repetitive mTBI. Exposure to blast overpressure from im ...[more]

PMID: 32094584

Similar Datasets

Project description:Chlorpyrifos (CPF), one of the most widely-used organophosphorus (OP) insecticides in agriculture, is degraded in the field to its oxon form, chlorpyrifos-oxon (CPO), which can represent a significant contaminant in exposures to adults and children. CPO is also responsible for the acetylcholinesterase (AChE) inhibition associated with CPF exposures; CPF is converted by liver CYP450 enzymes to CPO, which binds to and inhibits AChE and other serine active-site esterases, lipases and proteases. Young children represent a particularly susceptible population for exposure to CPF and CPO, in part because levels of the plasma enzyme, paraoxonase (PON1), which hydrolyzes CPO, are very low during early development. While a number of studies have demonstrated developmental neurotoxicity associated with CPF exposure, including effects at or below the threshold levels for AChE inhibition, it is unclear whether these effects were due directly to CPF or to its active metabolite, CPO. PON1 knockout (PON1-/-) mice, which lack PON1, represent a highly sensitive mouse model for toxicity associated with exposure to CPF or CPO. To examine the neurobehavioral consequences of CPO exposure during postnatal development, PON1-/- mice were exposed daily from PND 4 to PND 21 to CPO at 0.15, 0.18, or 0.25 mg/kg/d. A neurobehavioral test battery did not reveal significant effects of CPO on early reflex development, motor coordination, pre-pulse inhibition of startle, startle amplitude, open field behavior, or learning and memory in the contextual fear conditioning, Morris water maze, or water radial-arm maze tests. However, body weight gain and startle latency were significantly affected by exposure to 0.25 mg/kg/d CPO. Additionally, from PNDs 15-20 the mice exposed repeatedly to CPO at all three doses exhibited a dose-related transient hyperkinesis in the 20-min period following CPO administration, suggesting possible effects on catecholaminergic neurotransmission. Our previous study demonstrated wide-ranging effects of neonatal CPO exposure on gene expression in the brain and on brain AChE inhibition, and modulation of both of these effects by the PON1(Q192R) polymorphism. The current study indicates that the neurobehavioral consequences of these effects are more elusive, and suggests that alternative neurobehavioral tests might be warranted, such as tests of social interactions, age-dependent effects on learning and memory, or tests designed specifically to assess dopaminergic or noradrenergic function.

Project description:Blast neurotrauma has been linked to impairments in higher-order cognitive functions, including memory, attention, and mood. Current literature is limited to a single overpressure exposure or repeated exposures at the same level of overpressure. In this study, a rodent model of primary blast neurotrauma was employed to determine the pressure at which acute and chronic neurological alterations occurred. Three pressure magnitudes (low, moderate and high) were used to evaluate injury thresholds. A biology shock tube (BST) was used to simulate shock waves with overpressures of 60 kPa, 90 kPa and 120 kPa respectively. Neurological behavior of the rats was assessed by the Multi-Conditioning System (MCS) at 1 d, 7 d, 28 d and 90 d after shock wave exposure. Serum dopamine (DA), 5-hydroxytryptamine (5-HT), brain-derived neurotrophic factor (BDNF) and gamma-aminobutyric acid (GABA) were measured at the same time points. The proteomic analysis was conducted to identify potentially vulnerable cellular and molecule targets of serum in the immediate post-exposure period. Results revealed that: (1) Anxiety-like behavior increased significantly at 1 d post-exposure in the medium and high overpressure (90 kPa, 120 kPa) groups, returned to baseline at 7 days, and anxiety-like behavior in the high overpressure groups re-emerged at 28 d and 90 d. (2) High overpressure (120 kPa) impaired learning and memory in the immediate post-exposure period. (3) The serum DA levels decreased significantly at 1 d post-exposure in the medium and high overpressure groups; The 5-HT levels decreased significantly at 1 d and 90 d in the high overpressure groups; The BDNF levels decreased significantly at 90 d in the high overpressure groups. (4) Proteomic analysis identified 38, 306, and 57 differentially expressed proteins in serum following low, medium and high overpressure exposures, respectively. Two co-expressed proteins were validated. Functional analysis revealed significant enrichment of 1121, 2096, and 1121 Gene Ontology (GO) items and 33, 47, and 26 Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, indicating extensive molecular responses to overpressure in the early phase. These findings suggest that exposure, even at moderate levels, can induce persistent neurobehavioral and molecular alterations, highlighting the need for further research into the long-term consequences of blast neurotrauma.

Project description:Phthalates are a family of synthetic chemicals that are used in producing a variety of consumer products. Di-(2-ethylhexyl) phthalate (DEHP) is an widely used phthalate and poses a public health concern. Prenatal exposure to DEHP has been shown to induce premature reproductive senescence in animal studies. In this study, we tested the hypothesis that prenatal exposure to DEHP impairs neurobehavior and recognition memory in her male offspring and we investigated one possible mechanism-oxidative damage in the hippocampus. Pregnant CD-1 female mice were orally administered 200 μg, 500 mg, or 750 mg/kg/day DEHP or vehicle from gestational day 11 until birth. The neurobehavioral impact of the prenatal DEHP exposure was assessed at the ages of 16-22 months. Elevated plus maze and open field tests were used to measure anxiety levels. Y-maze and novel object recognition tests were employed to measure memory function. The oxidative damage in the hippocampus was measured by the levels of oxidative DNA damage and by Spatial light interference microscopic counting of hippocampal neurons. Adult male mice that were prenatally exposed to DEHP exhibited anxious behaviors and impaired spatial and short-term recognition memory. The number of hippocampal pyramidal neurons was significantly decreased in the DEHP mice. Furthermore, DEHP mice expressed remarkably high levels of cyclooxygenase-2, 8-hydroxyguanine, and thymidine glycol in their hippocampal neurons. DEHP mice also had lower circulating testosterone concentrations and displayed a weaker immunoreactivity than the control mice to androgen receptor expression in the brain. This study found that prenatal exposure to DEHP caused elevated anxiety behavior and impaired recognition memory. These behavioral changes may originate from neurodegeneration caused by oxidative damage and inflammation in the hippocampus. Decreased circulating testosterone concentrations and decreased expression of androgen receptor in the brain also may be factors contributing to the impaired neurobehavior in the DEHP mice.

Dataset Information

Brain and blood biomarkers of tauopathy and neuronal injury in humans and rats with neurobehavioral syndromes following blast exposure.

Publications

Brain and blood biomarkers of tauopathy and neuronal injury in humans and rats with neurobehavioral syndromes following blast exposure.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets