Imaging Macrophage Activity in the Brain by Using Ultrasmall Particles of Iron Oxide
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* Jeff W.M. Bulte
* Joseph A. Frank

We have read with great interest the two articles by Dousset et al reporting on the use of ultrasmall particles of iron oxide (USPIO) to detect macrophage activity in a rat model of experimental autoimmune encephalomyelitis (EAE) (1, 2). Iron oxides have now proved to be extremely sensitive contrast agents for MR imaging of blood-brain– barrier (BBB) disruption (3), with the exact cellular distribution within the brain parenchyma dependent on the type of particle (4).

We are concerned that using the term “imaging of macrophage activity” is misleading, because it suggests uptake of USPIO in brain macrophages, which was not shown to occur in either of the articles by Dousset et al. Instead, the presented histopathologic characteristics, including iron-specific Prussian Blue stains and electron micrographs, demonstrate uptake of USPIO in endothelial cells (not macrophages), most likely as a result of a leaky BBB. Because such a leaky BBB is caused indirectly by the presence of macrophages, the term “imaging of macrophage activity” in itself is not technically incorrect, but it should have been made clear that it refers to the indirect effects of macrophages on the BBB.

As the authors point out in their articles, the integrity of the BBB can be a very transient and dynamic process. Therefore, the momentary lack of Gd-DOTA enhancement during the first 10 minutes after injection should not lead to a conclusion that no defects in the BBB were present over an extended period, with the implication that the USPIO must have been transported into the brain via cells (including macrophages). The blood half-life of USPIO in rats is over 5 hours; the prolonged intravascular presence of the particles offers a far greater window of opportunity to enter the brain through a momentary defect in the BBB (5).

Unlike the available mouse EAE models and the human disease multiple sclerosis (MS), the Lewis rat EAE model is histopathologically characterized by an abundance of macrophages with relatively few T cells present. It remains to be seen if the histopathologic observations in current ongoing clinical trials with USPIO in MS patients will be comparable with those obtained in the rat. If they turn out to be comparable, then it supports the hypothesis that the USPIO brain uptake is nonspecific through a leaky BBB, irrespective of the predominant inflammatory cell type. This very interesting article deserves further studies, but caution should be taken when interpreting the imaging findings.

## References

1.  Dousset V, Ballarino L, Delalande C, et al. **Comparison of ultrasmall particles of iron oxide (USPIO)-enhanced T2-weighted, conventional T2-weighted, and gadolinium-enhanced T1-weighted MR images in rats with experimental autoimmune encephalomyelitis.** AJNR Am J Neuroradiol 1999;20:223-227
    
    [Abstract/FREE Full Text](http://www.ajnr.org/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6NDoiYWpuciI7czo1OiJyZXNpZCI7czo4OiIyMC8yLzIyMyI7czo0OiJhdG9tIjtzOjIwOiIvYWpuci8yMS85LzE3NjguYXRvbSI7fXM6ODoiZnJhZ21lbnQiO3M6MDoiIjt9) 

2.  Dousset V, Delalande C, Ballarino L, et al. **In vivo macrophage activity imaging in the central nervous system detected by magnetic resonance.** Magn Reson Med 1999;41:329-333
    
    [CrossRef](http://www.ajnr.org/lookup/external-ref?access_num=10.1002/(SICI)1522-2594(199902)41:2<329::AID-MRM17>3.0.CO;2-Z&link_type=DOI) 
    
    [PubMed](http://www.ajnr.org/lookup/external-ref?access_num=10080281&link_type=MED&atom=%2Fajnr%2F21%2F9%2F1768.atom) 
    
    [Web of Science](http://www.ajnr.org/lookup/external-ref?access_num=000078804500017&link_type=ISI) 

3.  Bulte JWM, DeJonge MWA, Kamman RL, et al. **Dextran-magnetite particles: contrast-enhanced MRI of blood-brain barrier disruption in a rat model.** Magn Reson Med 1992;23:215-223
    
    [PubMed](http://www.ajnr.org/lookup/external-ref?access_num=1372384&link_type=MED&atom=%2Fajnr%2F21%2F9%2F1768.atom) 

4.  Muldoon LL, Pagel MA, Kroll RA, Roman-Goldstein S, Jones RS, Neuwelt EA. **A physiological barrier distal to the anatomic blood-brain barrier in a rat model of transvascular delivery.** AJNR Am J Neuroradiol 1999;20:217-222
    
    [Abstract/FREE Full Text](http://www.ajnr.org/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6NDoiYWpuciI7czo1OiJyZXNpZCI7czo4OiIyMC8yLzIxNyI7czo0OiJhdG9tIjtzOjIwOiIvYWpuci8yMS85LzE3NjguYXRvbSI7fXM6ODoiZnJhZ21lbnQiO3M6MDoiIjt9) 

5.  Xu S, Jordan EK, Brocke S, et al. **Study of relapsing remitting experimental allergic encephalomyelitis SJL mouse model using MION-46L enhanced in vivo MRI: early histopathologic correlation.** J Neurosci Res 1998;52:549-558
    
    [CrossRef](http://www.ajnr.org/lookup/external-ref?access_num=10.1002/(SICI)1097-4547(19980601)52:5<549::AID-JNR7>3.0.CO;2-C&link_type=DOI) 
    
    [PubMed](http://www.ajnr.org/lookup/external-ref?access_num=9632311&link_type=MED&atom=%2Fajnr%2F21%2F9%2F1768.atom) 
    
    [Web of Science](http://www.ajnr.org/lookup/external-ref?access_num=000073900300007&link_type=ISI) 

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