Characterisation of interface astroglial scarring in the human brain after blast exposure: a post-mortem case series

Shively, Sharon; Horkayne‐Szakaly, Iren; Jones, Robert; Kelly, James P.; Armstrong, Regina C.; Perl, Daniel P.

doi:10.1016/s1474-4422(16)30057-6

Cited by 176 publications

(166 citation statements)

References 36 publications

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“…In addition, many soldiers who suffer mild TBIs later develop posttraumatic stress disorders and progressive dementia. Some studies argue that these signature injuries of the recent conflicts in Afghanistan and Iraq are the result of exposure to blast waves from improvised explosive devices (34,(64)(65)(66)(67). Similar to AD, biochemical analyses of NFTs isolated from CTE patients have shown that these aggregates consist of both 3R and 4R tau isoforms (24).…”

Section: Discussionmentioning

confidence: 99%

Tau prions from Alzheimer’s disease and chronic traumatic encephalopathy patients propagate in cultured cells

Woerman

Aoyagi

Patel

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

148

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Tau prions are thought to aggregate in the central nervous system, resulting in neurodegeneration. Among the tauopathies, Alzheimer's disease (AD) is the most common, whereas argyrophilic grain disease (AGD), corticobasal degeneration (CBD), chronic traumatic encephalopathy (CTE), Pick's disease (PiD), and progressive supranuclear palsy (PSP) are less prevalent. Brain extracts from deceased individuals with PiD, a neurodegenerative disorder characterized by three-repeat (3R) tau prions, were used to infect HEK293T cells expressing 3R tau fused to yellow fluorescent protein (YFP). Extracts from AGD, CBD, and PSP patient samples, which contain four-repeat (4R) tau prions, were transmitted to HEK293 cells expressing 4R tau fused to YFP. These studies demonstrated that prion propagation in HEK cells requires isoform pairing between the infecting prion and the recipient substrate. Interestingly, tau aggregates in AD and CTE, containing both 3R and 4R isoforms, were unable to robustly infect either 3R-or 4R-expressing cells. However, AD and CTE prions were able to replicate in HEK293T cells expressing both 3R and 4R tau. Unexpectedly, increasing the level of 4R isoform expression alone supported the propagation of both AD and CTE prions. These results allowed us to determine the levels of tau prions in AD and CTE brain extracts.argyrophilic grain disease | corticobasal degeneration | Pick's disease | progressive supranuclear palsy | tauopathies

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Section: Discussionmentioning

confidence: 99%

Tau prions from Alzheimer’s disease and chronic traumatic encephalopathy patients propagate in cultured cells

Woerman

Aoyagi

Patel

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

148

130

View full text Add to dashboard Cite

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“…Since larger aggregates of p-tau would not be as free to move readily through the brain ECS by diffusion as unbound monomers, such aggregates likely become trapped within the tissue, particularly the tissue space bordering venules and large veins; this sequence of events would be expected to further impede the subsequent clearance of p-tau and other waste constituents over time. Interestingly, military personnel exposed to blast shockwaves (e.g., from explosive devices) also show a characteristic pattern of GFAP and p-tau immunoreactivity with prominent astroglial scarring at brain-fluid interfaces including the subpial region and perivascular spaces [156].…”

Section: Cns Pathologies and Disturbances Of Brain Fluidsmentioning

confidence: 99%

The role of brain barriers in fluid movement in the CNS: is there a ‘glymphatic’ system?

et al. 2018

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Brain fluids are rigidly regulated to provide stable environments for neuronal function, e.g., low K + , Ca 2+ , and protein to optimise signalling and minimise neurotoxicity. At the same time, neuronal and astroglial waste must be promptly removed. The interstitial fluid (ISF) of the brain tissue and the cerebrospinal fluid (CSF) bathing the CNS are integral to this homeostasis and the idea of a glia-lymph or 'glymphatic' system for waste clearance from brain has developed over the last 5 years. This links bulk (convective) flow of CSF into brain along the outside of penetrating arteries, glia-mediated convective transport of fluid and solutes through the brain extracellular space (ECS) involving the aquaporin-4 (AQP4) water channel, and finally delivery of fluid to venules for clearance along peri-venous spaces. However, recent evidence favours important amendments to the 'glymphatic' hypothesis, particularly concerning the role of glia and transfer of solutes within the ECS. This review discusses studies which question the role of AQP4 in ISF flow and the lack of evidence for its ability to transport solutes; summarizes attributes of brain ECS that strongly favour the diffusion of small and large molecules without ISF flow; discusses work on hydraulic conductivity and the nature of the extracellular matrix which may impede fluid movement; and reconsiders the roles of the perivascular space (PVS) in CSF-ISF exchange and drainage. We also consider the extent to which CSF-ISF exchange is possible and desirable, the impact of neuropathology on fluid drainage, and why using CSF as a proxy measure of brain components or drug delivery is problematic. We propose that new work and key historical studies both support the concept of a perivascular fluid system, whereby CSF enters the brain via PVS convective flow or dispersion along larger caliber arteries/arterioles, diffusion predominantly regulates CSF/ISF exchange at the level of the neurovascular unit associated with CNS microvessels, and, finally, a mixture of CSF/ISF/waste products is normally cleared along the PVS of venules/veins as well as other pathways; such a system may or may not constitute a true 'circulation', but, at the least, suggests a comprehensive re-evaluation of the previously proposed 'glymphatic' concepts in favour of a new system better taking into account basic cerebrovascular physiology and fluid transport considerations.

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“…These findings are in concordance with postmortem studies of boxers and military personnel who had repetitive trauma to the head, showing increased astroglial activation. 3,23 Experimental and postmortem case-control studies suggest that athletes who have been exposed to repetitive head trauma are at increased risk of developing brain pathology, such as Ab deposition and tau pathology. 3,4,12,13 In the context of AD, numerous studies have shown that reduced CSF Ab42 concentrations correlate strongly with positive amyloid PET finding, 24 and a recent study also suggests that the reduction in CSF Ab42 is an earlier indicator of cerebral Ab deposition than amyloid PET.…”

mentioning

confidence: 99%

Astroglial activation and altered amyloid metabolism in human repetitive concussion

et al. 2017

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Objective: To determine whether postconcussion syndrome (PCS) due to repetitive concussive traumatic brain injury (rcTBI) is associated with CSF biomarker evidence of astroglial activation, amyloid deposition, and blood-brain barrier (BBB) impairment.Methods: A total of 47 participants (28 professional athletes with PCS and 19 controls) were assessed with lumbar puncture (median 1.5 years, range 0.25-12 years after last concussion), standard MRI of the brain, and Rivermead Post-Concussion Symptoms Questionnaire (RPQ). The main outcome measures were CSF concentrations of astroglial activation markers (glial fibrillary acidic protein [GFAP] and YKL-40), markers reflecting amyloid precursor protein metabolism (Ab38, Ab40, Ab42, sAPPa, and sAPPb), and BBB function (CSF:serum albumin ratio).Results: Nine of the 28 athletes returned to play within a year, while 19 had persistent PCS .1 year. Athletes with PCS .1 year had higher RPQ scores and number of concussions than athletes with PCS ,1 year. Median concentrations of GFAP and YKL-40 were higher in athletes with PCS .1 year compared with controls, although with an overlap between the groups. YKL-40 correlated with RPQ score and the lifetime number of concussions. Athletes with rcTBI had lower concentrations of Ab40 and Ab42 than controls. The CSF:serum albumin ratio was unaltered.Conclusions: This study suggests that PCS may be associated with biomarker evidence of astroglial activation and b-amyloid (Ab) dysmetabolism in the brain. There was no clear evidence of Ab deposition as Ab40 and Ab42 were reduced in parallel. The CSF:serum albumin ratio was unaltered, suggesting that the BBB is largely intact in PCS. Neurology ® 2017;88:1400-1407 GLOSSARY Ab 5 b-amyloid; AD 5 Alzheimer disease; APP 5 amyloid precursor protein; BBB 5 blood-brain barrier; cTBI 5 concussive traumatic brain injury; CTE 5 chronic traumatic encephalopathy; DSM-IV 5 Diagnostic and Statistical Manual of Mental Disorders, 4th edition; GFAP 5 glial fibrillary acidic protein; LP 5 lumbar puncture; NFL 5 neurofilament light; PCS 5 postconcussion syndrome; rcTBI 5 repetitive concussive traumatic brain injury; RPQ 5 Rivermead Post-Concussion Symptoms Questionnaire; sAPPa 5 a-cleaved soluble amyloid precursor protein; sAPPb 5 b-cleaved soluble amyloid precursor protein; TBI 5 traumatic brain injury.Concussion is a type of mild traumatic brain injury (TBI) (concussive TBI [cTBI]) caused by rapid rotational acceleration of the head, which causes the brain to deform, resulting in tissue damage, particularly to vulnerable white matter axons.1 While most individuals with cTBI recover completely within days to weeks, about 10%-15% of individuals display persistent neurobehavioral symptoms for more than 3 months, a condition referred to as postconcussion syndrome (PCS).2 A proportion of individuals exposed to repetitive concussive TBI (rcTBI) may develop a progressive neurodegenerative condition referred to as chronic traumatic encephalopathy (CTE).3,4 CTE is characterized by tau and, less consistently...

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Characterisation of interface astroglial scarring in the human brain after blast exposure: a post-mortem case series

Abstract: Defense Health Program of the United States Department of Defense.

Cited by 176 publications

References 36 publications

Tau prions from Alzheimer’s disease and chronic traumatic encephalopathy patients propagate in cultured cells

Tau prions from Alzheimer’s disease and chronic traumatic encephalopathy patients propagate in cultured cells

The role of brain barriers in fluid movement in the CNS: is there a ‘glymphatic’ system?

Astroglial activation and altered amyloid metabolism in human repetitive concussion

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