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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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Adjacent sections through the anterior corpus callosum of a typical blast case (Case 1; Table1) immunostained with an axonal injury marker (APP; a-b) and microglial marker (IBA1; c-d). b is enlargement of bracketed area in a and shows, in greater detail, abnormally swollen axons traveling in various directions. d is an enlargement of bracketed are in c taken through the border between healthy tissue and a patch of axonopathy. Insets in d are magnifications of microglial profiles indicated with arrows. Note the correspondence of axonopathy (a) with neuroinflammation (c) in the same patch of tissue and the transition between ramified and deramified/round microglia in the border between reactive and non-reactive tissue in (d). In Figure 2e-f, note that microglia has resting cytology and there are no appreciable differences between areas with APP (+) axonopathy and areas without. Size bars: 50 (a and c) and 20 (b and d) μm.
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Fig8: Adjacent sections through the anterior corpus callosum of a typical blast case (Case 1; Table1) immunostained with an axonal injury marker (APP; a-b) and microglial marker (IBA1; c-d). b is enlargement of bracketed area in a and shows, in greater detail, abnormally swollen axons traveling in various directions. d is an enlargement of bracketed are in c taken through the border between healthy tissue and a patch of axonopathy. Insets in d are magnifications of microglial profiles indicated with arrows. Note the correspondence of axonopathy (a) with neuroinflammation (c) in the same patch of tissue and the transition between ramified and deramified/round microglia in the border between reactive and non-reactive tissue in (d). In Figure 2e-f, note that microglia has resting cytology and there are no appreciable differences between areas with APP (+) axonopathy and areas without. Size bars: 50 (a and c) and 20 (b and d) μm.

Mentions: To explore the regional association of axonal abnormalities with neuroinflammatory responses in the brains of blast cases, we performed IHC for the microglial marker IBA1 or the astrocytic marker GFAP and compared such labeling with immunolabeling for APP on same or adjacent sections. Figure 8 shows evidence of colocalization of IBA1 (+) deramified/hypertrophic microglia with patches of abnormal APP (+) axons in the corpus callosum of an index case with blast history (Case 1). The best evidence of colocalization of APP (+) axonal abnormalities with activated microglia in blast cases is shown in double-labeling preparations as the one illustrated in Figure 2c-d (Case 1). A similar colocalization of hypertrophic, phagocytic microglia with APP (+) axonal abnormalities is seen in DAI associated with MVC (Figure 2a-b; Case 21). On the other hand, there is no evidence of microglial activation next to abnormal axons in cases of opiate overdose (Figure 2e-f; Case 7). In contrast to the colocalization of APP (+) axonal abnormalities with activated microglia in blast and MVC cases, there was no clear evidence for colocalization of such abnormalities with GFAP (+) reactive astrocytes.Figure 8


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)

Adjacent sections through the anterior corpus callosum of a typical blast case (Case 1; Table1) immunostained with an axonal injury marker (APP; a-b) and microglial marker (IBA1; c-d). b is enlargement of bracketed area in a and shows, in greater detail, abnormally swollen axons traveling in various directions. d is an enlargement of bracketed are in c taken through the border between healthy tissue and a patch of axonopathy. Insets in d are magnifications of microglial profiles indicated with arrows. Note the correspondence of axonopathy (a) with neuroinflammation (c) in the same patch of tissue and the transition between ramified and deramified/round microglia in the border between reactive and non-reactive tissue in (d). In Figure 2e-f, note that microglia has resting cytology and there are no appreciable differences between areas with APP (+) axonopathy and areas without. Size bars: 50 (a and c) and 20 (b and d) μm.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Fig8: Adjacent sections through the anterior corpus callosum of a typical blast case (Case 1; Table1) immunostained with an axonal injury marker (APP; a-b) and microglial marker (IBA1; c-d). b is enlargement of bracketed area in a and shows, in greater detail, abnormally swollen axons traveling in various directions. d is an enlargement of bracketed are in c taken through the border between healthy tissue and a patch of axonopathy. Insets in d are magnifications of microglial profiles indicated with arrows. Note the correspondence of axonopathy (a) with neuroinflammation (c) in the same patch of tissue and the transition between ramified and deramified/round microglia in the border between reactive and non-reactive tissue in (d). In Figure 2e-f, note that microglia has resting cytology and there are no appreciable differences between areas with APP (+) axonopathy and areas without. Size bars: 50 (a and c) and 20 (b and d) μm.
Mentions: To explore the regional association of axonal abnormalities with neuroinflammatory responses in the brains of blast cases, we performed IHC for the microglial marker IBA1 or the astrocytic marker GFAP and compared such labeling with immunolabeling for APP on same or adjacent sections. Figure 8 shows evidence of colocalization of IBA1 (+) deramified/hypertrophic microglia with patches of abnormal APP (+) axons in the corpus callosum of an index case with blast history (Case 1). The best evidence of colocalization of APP (+) axonal abnormalities with activated microglia in blast cases is shown in double-labeling preparations as the one illustrated in Figure 2c-d (Case 1). A similar colocalization of hypertrophic, phagocytic microglia with APP (+) axonal abnormalities is seen in DAI associated with MVC (Figure 2a-b; Case 21). On the other hand, there is no evidence of microglial activation next to abnormal axons in cases of opiate overdose (Figure 2e-f; Case 7). In contrast to the colocalization of APP (+) axonal abnormalities with activated microglia in blast and MVC cases, there was no clear evidence for colocalization of such abnormalities with GFAP (+) reactive astrocytes.Figure 8

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