Higher exosomal phosphorylated tau and total tau among veterans with combat-related repetitive chronic mild traumatic brain injury

Kenney, Kimbra; Qu, Bao-Xi; Lai, Chen; Devoto, Christina; Motamedi, Vida; Walker, William C.; Levin, Harvey S.; Nolen, Tracy L.; Wilde, Elisabeth A.; Diaz‐Arrastia, Ramon; Gill, Jessica

doi:10.1080/02699052.2018.1483530

Cited by 83 publications

(96 citation statements)

References 56 publications

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“…19,20 It seems possible that plasma tau and Ab42 may not be sufficiently sensitive to TBI many years after concussion or repetitive subconcussive head impact. Exosomal tau, however, which has been shown to be sensitive to concussion many years post-injury, 57,58 has been shown to be related to processing speed and verbal learning and memory 58 and may be a better biomarker of TBI and recovery than plasma tau. 57 Although the relationship between plasma biomarkers and white matter integrity was not statistically significant after correction for multiple comparisons, there were consistent trends explaining roughly 20-30% of the variance between the biomarkers and ROIs that are worth highlighting.…”

Section: Discussionmentioning

confidence: 99%

“…Exosomal tau, however, which has been shown to be sensitive to concussion many years post-injury, 57,58 has been shown to be related to processing speed and verbal learning and memory 58 and may be a better biomarker of TBI and recovery than plasma tau. 57 Although the relationship between plasma biomarkers and white matter integrity was not statistically significant after correction for multiple comparisons, there were consistent trends explaining roughly 20-30% of the variance between the biomarkers and ROIs that are worth highlighting. In patients with moderate, severe, or penetrating TBI, higher tau and Ab42 tended to be related to higher FA and lower MD, RD, and AD.…”

Section: Discussionmentioning

confidence: 99%

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Plasma Tau and Amyloid Are Not Reliably Related to Injury Characteristics, Neuropsychological Performance, or White Matter Integrity in Service Members with a History of Traumatic Brain Injury

Yeh

Gill

French

et al. 2019

Journal of Neurotrauma

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The aim of this study was to examine the relationship between plasma tau and amyloid beta-42 (Ab42), neuropsychological functioning, and white matter integrity in U.S. military service members with (n = 155) and without (n = 42) a history of uncomplicated mild (n = 83), complicated mild (n = 26), or moderate, severe, or penetrating (n = 46) traumatic brain injury (TBI). We hypothesized that higher levels of tau and Ab42 would be related to reduced neurocognitive performance and white matter integrity. Participants were enrolled prospectively from Walter Reed National Military Medical Center. Participants completed a blood draw, neuropsychological assessment, and diffusion tensor imaging (General Electric 3T) of the whole brain. From 20 neuropsychological test scores, five cognitive domain scores were computed. Measures of fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) were generated for 18 regions of interest (ROIs). There was no relationship found between the plasma biomarkers and neurocognitive performance in any of the three TBI groups (all ps >0.05; all R 2 changes <0.146). Although not reaching statistical significance after correction for multiple comparisons, higher tau and Ab42 tended to be related to higher FA and lower MD, RD, and AD in patients with a history of moderate, severe, or penetrating TBI. There was no consistent relationship between either of the biomarkers and white matter integrity in the complicated and uncomplicated mild TBI groups. In addition, there was no significant relationship between the biomarkers and age, education, sex, race, bodily injury severity, time since injury, TBI severity, or number of TBIs (all ps >0.15). Future investigation in larger samples of moderate, severe, and penetrating TBI are needed. Other plasma biomarkers, including phosphorylated tau, exosomal tau, and interleukin-10, may be more promising measures to use in the diagnosis, management, and treatment of TBI.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Plasma Tau and Amyloid Are Not Reliably Related to Injury Characteristics, Neuropsychological Performance, or White Matter Integrity in Service Members with a History of Traumatic Brain Injury

Yeh

Gill

French

et al. 2019

Journal of Neurotrauma

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“…Central nervous system-enriched proteins, such as neurofilament light chain (Nf-L), tau, and glial fibrillary protein (GFAP) have been used as objective measurements to identify TBI [7,8]. Similarly, ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) and amyloid precursor protein (APP), the precursor of amyloid beta (Aβ) peptides, have been identified in peripheral blood collected weeks-months after exposure [9]. These biomarkers have been robust identifiers within the context of chronic paradigms relevant to overpressure as well as TBI.…”

Section: A1111111111 A1111111111 A1111111111 A1111111111 A1111111111mentioning

confidence: 99%

Brain-related proteins as serum biomarkers of acute, subconcussive blast overpressure exposure: A cohort study of military personnel

et al. 2019

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Repeated exposure to blast overpressure remains a major cause of adverse health for military personnel who, as a consequence, are at a higher risk for neurodegenerative disease and suicide. Acute, early tracking of blast related effects holds the promise of rapid health assessment prior to onset of chronic problems. Current techniques used to determine blastrelated effects rely upon reporting of symptomology similar to that of concussion and neurocognitive assessment relevant to operational decrement. Here, we describe the results of a cross sectional study with pared observations. The concentration of multiple TBI-related proteins was tested in serum collected within one hour of blast exposure as a quantitative and minimally invasive strategy to augment assessment of blast-exposure effects that are associated with concussion-like symptomology and reaction time decrements. We determined that median simple reaction time (SRT) was slowed in accordance with serum Nf-L, tau, Aβ-40, and Aβ-42 elevation after overpressure exposure. In contrast, median levels of serum GFAP decreased. Individual, inter-subject analysis revealed positive correlations between changes in Nf-L and GFAP, and in Aβ-40 compared to Aβ-42. The change in Nf-L was negatively associated with tau, Aβ-40, and Aβ-42. Participants reported experiencing headaches, dizziness and taking longer to think. Dizziness was associated with reaction time decrements, GFAP or NfL suppression, as well as Aβ peptide elevation. UCH-L1 elevation had a weak association with mTBI/concussion history. Multiplexed serum biomarker quantitation, coupled with reaction time assessment and symptomology determined before and after blast exposure, may serve as a platform for tracking adverse effects in the absence of a head wound or diagnosed concussion. We propose further evaluation of serum biomarkers, which are often associated with TBI, in the context of acute operational blast exposures.

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“…In fact, the literature indicates neither amyloid plaques, nor neurofibrillary tangle (NFT) deposits, are unique to AD, as suggested in their abstract [ 119 ], since these pathologies are also paired in other neurodegenerative states, such as post-stroke syndromes [ 268 ], Parkinson’s disease (PD) [ 203 ], traumatic brain injury (TBI) [ 140 ], HIV-dementia [ 288 ], Lewy body dementia [ 54 ] and lead poisoning [ 158 ]. Indeed, Alois Alzheimer and his contemporaries noted similarities in the clinical and pathological presentations of syphilitic dementia and AD [ 171 ].…”

Section: Introductionmentioning

confidence: 99%

Questions concerning the role of amyloid-β in the definition, aetiology and diagnosis of Alzheimer’s disease

2018

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The dominant hypothesis of Alzheimer’s disease (AD) aetiology, the neuropathological guidelines for diagnosing AD and the majority of high-profile therapeutic efforts, in both research and in clinical practice, have been built around one possible causal factor, amyloid-β (Aβ). However, the causal link between Aβ and AD remains unproven. Here, in the context of a detailed assessment of historical and contemporary studies, we raise critical questions regarding the role of Aβ in the definition, diagnosis and aetiology of AD. We illustrate that a holistic view of the available data does not support an unequivocal conclusion that Aβ has a central or unique role in AD. Instead, the data suggest alternative views of AD aetiology are potentially valid, at this time. We propose that an unbiased way forward for the field, beyond the current Aβ-centric approach, without excluding a role for Aβ, is required to come to an accurate understanding of AD dementia and, ultimately, an effective treatment.Electronic supplementary materialThe online version of this article (10.1007/s00401-018-1918-8) contains supplementary material, which is available to authorized users.

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Higher exosomal phosphorylated tau and total tau among veterans with combat-related repetitive chronic mild traumatic brain injury

Abstract: rTBI is associated with elevations of exosomal p-tau and exosomal tau, suggesting that blood-based exosomes may provide a peripheral source of informative, centrally derived biomarkers in remote mTBI and that rTBI may contribute to chronic neuropsychological symptoms.

Cited by 83 publications

References 56 publications

Plasma Tau and Amyloid Are Not Reliably Related to Injury Characteristics, Neuropsychological Performance, or White Matter Integrity in Service Members with a History of Traumatic Brain Injury

Plasma Tau and Amyloid Are Not Reliably Related to Injury Characteristics, Neuropsychological Performance, or White Matter Integrity in Service Members with a History of Traumatic Brain Injury

Brain-related proteins as serum biomarkers of acute, subconcussive blast overpressure exposure: A cohort study of military personnel

Questions concerning the role of amyloid-β in the definition, aetiology and diagnosis of Alzheimer’s disease

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