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The problem of axonal injury in the brains of veterans with histories of blast exposure.

Ryu J, Horkayne-Szakaly I, Xu L, Pletnikova O, Leri F, Eberhart C, Troncoso JC, Koliatsos VE - Acta Neuropathol Commun (2014)

Bottom Line: In cases with blast history, we found APP (+) axonal abnormalities in several brain sites, especially the medial dorsal frontal white matter.Opiate overdose cases also showed APP (+) axonal abnormalities, but the intensity of these lesions was lower compared to cases with blast histories and there was no clear association of such lesions with microglial activation.Our findings demonstrate that many cases with history of blast exposure are featured by APP (+) axonopathy that may be related to blast exposure, but an important role for opiate overdose, antemortem anoxia, and concurrent blunt TBI events in war theater or elsewhere cannot be discounted.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Division of Neuropathology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. jryu4@jhmi.edu.

ABSTRACT

Introduction: Blast injury to brain, a hundred-year old problem with poorly characterized neuropathology, has resurfaced as health concern in recent deployments in Iraq and Afghanistan. To characterize the neuropathology of blast injury, we examined the brains of veterans for the presence of amyloid precursor protein (APP)-positive axonal swellings typical of diffuse axonal injury (DAI) and compared them to healthy controls as well as controls with opiate overdose, anoxic-ischemic encephalopathy, and non-blast TBI (falls and motor vehicle crashes).

Results: In cases with blast history, we found APP (+) axonal abnormalities in several brain sites, especially the medial dorsal frontal white matter. In white matter, these abnormalities were featured primarily by clusters of axonal spheroids or varicosities in a honeycomb pattern with perivascular distribution. Axonal abnormalities colocalized with IBA1 (+) reactive microglia and had an appearance that was distinct from classical DAI encountered in TBI due to motor vehicle crashes. Opiate overdose cases also showed APP (+) axonal abnormalities, but the intensity of these lesions was lower compared to cases with blast histories and there was no clear association of such lesions with microglial activation.

Conclusions: Our findings demonstrate that many cases with history of blast exposure are featured by APP (+) axonopathy that may be related to blast exposure, but an important role for opiate overdose, antemortem anoxia, and concurrent blunt TBI events in war theater or elsewhere cannot be discounted.

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Related in: MedlinePlus

Sections immunostained for concomitant localization of APP and IBA1 epitopes in representative cases of MVC (Case 21; a-b), blast (Case 1; c-d), and opiate overdose (Case 7; e-f). APP (brown) and IBA1 (blue) was detected sequentially by DAB and Vector blue, respectively, as described in Methods. Note that, in MVC (a-b) and blast (c-d) APP (+) swellings and bulbs colocalise with deramified or phagocytic microglia, whereas in opiate overdose (e-f) they do not. Panels b, d, and f are magnifications of framed areas in a,c, and e, respectively. Size bars: 50 (a, c and e) and 100 (b, d, and f) μm.
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Fig2: Sections immunostained for concomitant localization of APP and IBA1 epitopes in representative cases of MVC (Case 21; a-b), blast (Case 1; c-d), and opiate overdose (Case 7; e-f). APP (brown) and IBA1 (blue) was detected sequentially by DAB and Vector blue, respectively, as described in Methods. Note that, in MVC (a-b) and blast (c-d) APP (+) swellings and bulbs colocalise with deramified or phagocytic microglia, whereas in opiate overdose (e-f) they do not. Panels b, d, and f are magnifications of framed areas in a,c, and e, respectively. Size bars: 50 (a, c and e) and 100 (b, d, and f) μm.

Mentions: In some cases with blast histories, groups of abnormally swollen APP (+) axons and axon bulbs were also encountered in the corpus callosum (Additional file 1: Figure S1 for Case 3 but also Figure 2 for Case 1), the superior cerebellar peduncle, and cerebellum. In the cerebellum, axonal swellings were often seen in the deep white matter next to deep nuclei and also in the form of classical retraction balls in the granule cell layer next to Purkinje cell bodies. These retraction balls were eosinophilic, argyrophilic, and APP-immunoreactive, and were also filled with phosphorylated neurofilaments (Additional file 2: Figure S2 for Case 3). One of these cases, e.g. the one illustrated in Additional file 1: Figure S1 and Additional file 2: Figure S2, had suffered traumatic events other than blast relatively near the time of death. APP (+) axonal swellings were occasionally encountered also in internal capsule, striatopallidal pencils, and thalamic striae.Figure 2


The problem of axonal injury in the brains of veterans with histories of blast exposure.

Ryu J, Horkayne-Szakaly I, Xu L, Pletnikova O, Leri F, Eberhart C, Troncoso JC, Koliatsos VE - Acta Neuropathol Commun (2014)

Sections immunostained for concomitant localization of APP and IBA1 epitopes in representative cases of MVC (Case 21; a-b), blast (Case 1; c-d), and opiate overdose (Case 7; e-f). APP (brown) and IBA1 (blue) was detected sequentially by DAB and Vector blue, respectively, as described in Methods. Note that, in MVC (a-b) and blast (c-d) APP (+) swellings and bulbs colocalise with deramified or phagocytic microglia, whereas in opiate overdose (e-f) they do not. Panels b, d, and f are magnifications of framed areas in a,c, and e, respectively. Size bars: 50 (a, c and e) and 100 (b, d, and f) μm.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4260204&req=5

Fig2: Sections immunostained for concomitant localization of APP and IBA1 epitopes in representative cases of MVC (Case 21; a-b), blast (Case 1; c-d), and opiate overdose (Case 7; e-f). APP (brown) and IBA1 (blue) was detected sequentially by DAB and Vector blue, respectively, as described in Methods. Note that, in MVC (a-b) and blast (c-d) APP (+) swellings and bulbs colocalise with deramified or phagocytic microglia, whereas in opiate overdose (e-f) they do not. Panels b, d, and f are magnifications of framed areas in a,c, and e, respectively. Size bars: 50 (a, c and e) and 100 (b, d, and f) μm.
Mentions: In some cases with blast histories, groups of abnormally swollen APP (+) axons and axon bulbs were also encountered in the corpus callosum (Additional file 1: Figure S1 for Case 3 but also Figure 2 for Case 1), the superior cerebellar peduncle, and cerebellum. In the cerebellum, axonal swellings were often seen in the deep white matter next to deep nuclei and also in the form of classical retraction balls in the granule cell layer next to Purkinje cell bodies. These retraction balls were eosinophilic, argyrophilic, and APP-immunoreactive, and were also filled with phosphorylated neurofilaments (Additional file 2: Figure S2 for Case 3). One of these cases, e.g. the one illustrated in Additional file 1: Figure S1 and Additional file 2: Figure S2, had suffered traumatic events other than blast relatively near the time of death. APP (+) axonal swellings were occasionally encountered also in internal capsule, striatopallidal pencils, and thalamic striae.Figure 2

Bottom Line: In cases with blast history, we found APP (+) axonal abnormalities in several brain sites, especially the medial dorsal frontal white matter.Opiate overdose cases also showed APP (+) axonal abnormalities, but the intensity of these lesions was lower compared to cases with blast histories and there was no clear association of such lesions with microglial activation.Our findings demonstrate that many cases with history of blast exposure are featured by APP (+) axonopathy that may be related to blast exposure, but an important role for opiate overdose, antemortem anoxia, and concurrent blunt TBI events in war theater or elsewhere cannot be discounted.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Division of Neuropathology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. jryu4@jhmi.edu.

ABSTRACT

Introduction: Blast injury to brain, a hundred-year old problem with poorly characterized neuropathology, has resurfaced as health concern in recent deployments in Iraq and Afghanistan. To characterize the neuropathology of blast injury, we examined the brains of veterans for the presence of amyloid precursor protein (APP)-positive axonal swellings typical of diffuse axonal injury (DAI) and compared them to healthy controls as well as controls with opiate overdose, anoxic-ischemic encephalopathy, and non-blast TBI (falls and motor vehicle crashes).

Results: In cases with blast history, we found APP (+) axonal abnormalities in several brain sites, especially the medial dorsal frontal white matter. In white matter, these abnormalities were featured primarily by clusters of axonal spheroids or varicosities in a honeycomb pattern with perivascular distribution. Axonal abnormalities colocalized with IBA1 (+) reactive microglia and had an appearance that was distinct from classical DAI encountered in TBI due to motor vehicle crashes. Opiate overdose cases also showed APP (+) axonal abnormalities, but the intensity of these lesions was lower compared to cases with blast histories and there was no clear association of such lesions with microglial activation.

Conclusions: Our findings demonstrate that many cases with history of blast exposure are featured by APP (+) axonopathy that may be related to blast exposure, but an important role for opiate overdose, antemortem anoxia, and concurrent blunt TBI events in war theater or elsewhere cannot be discounted.

Show MeSH
Related in: MedlinePlus