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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

Stereological areal fraction analysis of APP-positive axonal injury signal in blast (n = 4) and methadone (n = 4) cases. Coronal sections through the frontal lobe were stained by APP N-terminal antibody (see Materials and Methods). Axon injury signal was counted (a) and analyzed by two-tail student’s t-test (b). Difference between blast and methadone cases was significant at P value 0.0195.
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Fig5: Stereological areal fraction analysis of APP-positive axonal injury signal in blast (n = 4) and methadone (n = 4) cases. Coronal sections through the frontal lobe were stained by APP N-terminal antibody (see Materials and Methods). Axon injury signal was counted (a) and analyzed by two-tail student’s t-test (b). Difference between blast and methadone cases was significant at P value 0.0195.

Mentions: Because 3 out of 4 blast cases with APP (+) axonal swellings had died of opiate overdose (Table 1), 6 additional cases with opiate overdose without blast exposure were analyzed as controls. In 5 out of 6 subjects, we observed a few APP (+) axonal abnormalities in the medial frontal white matter, corpus callosum and the internal capsule (Figure 4), but these pathologies were significantly less pronounced compared to the ones in blast injury cases. In one case of an 18-year old female (Case 11) who died from mixed overdose with antidepressants and opiates, we found extensive axonal abnormalities in patches throughout the white matter of frontal cortex. Based on the mixed nature of intoxication that may be associated with regulatory APP events [27] this brain was not included in the opiate overdose group for further stereological analysis, but was illustrated in supplementary figures (Additional file 3: Figure S3). When we analyzed the density of APP (+) axonal abnormalities in frontal cortex with stereology, there were significant differences between the blast (n = 4) and methadone (n = 4) groups (P = 0.0195; Figure 5). The honeycomb pattern of axonal injury with perivascular distribution (Figure 1) was not evident in methadone overdose cases.Figure 4


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)

Stereological areal fraction analysis of APP-positive axonal injury signal in blast (n = 4) and methadone (n = 4) cases. Coronal sections through the frontal lobe were stained by APP N-terminal antibody (see Materials and Methods). Axon injury signal was counted (a) and analyzed by two-tail student’s t-test (b). Difference between blast and methadone cases was significant at P value 0.0195.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Fig5: Stereological areal fraction analysis of APP-positive axonal injury signal in blast (n = 4) and methadone (n = 4) cases. Coronal sections through the frontal lobe were stained by APP N-terminal antibody (see Materials and Methods). Axon injury signal was counted (a) and analyzed by two-tail student’s t-test (b). Difference between blast and methadone cases was significant at P value 0.0195.
Mentions: Because 3 out of 4 blast cases with APP (+) axonal swellings had died of opiate overdose (Table 1), 6 additional cases with opiate overdose without blast exposure were analyzed as controls. In 5 out of 6 subjects, we observed a few APP (+) axonal abnormalities in the medial frontal white matter, corpus callosum and the internal capsule (Figure 4), but these pathologies were significantly less pronounced compared to the ones in blast injury cases. In one case of an 18-year old female (Case 11) who died from mixed overdose with antidepressants and opiates, we found extensive axonal abnormalities in patches throughout the white matter of frontal cortex. Based on the mixed nature of intoxication that may be associated with regulatory APP events [27] this brain was not included in the opiate overdose group for further stereological analysis, but was illustrated in supplementary figures (Additional file 3: Figure S3). When we analyzed the density of APP (+) axonal abnormalities in frontal cortex with stereology, there were significant differences between the blast (n = 4) and methadone (n = 4) groups (P = 0.0195; Figure 5). The honeycomb pattern of axonal injury with perivascular distribution (Figure 1) was not evident in methadone overdose cases.Figure 4

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