The histological demonstration of iron in Aβ plaques is important not only because of its possible role in the pathogenesis of the disease, but also because the Aβ-iron complex can be used as a mechanism of detection and progression of the disease by magnetic resonance imaging (MRI).
The detection of Alzheimer disease (AD) with noninvasive methods is a very active and important area of research. Recently, MRI has been used to detect Aβ plaques in vitro and in vivo, both with and without contrast agent (Benveniste et al., 1999; Wadghiri et al., 2003; Zhang et al., 2004; Jack et al., 2004; Lee at al., 2004; Vanhoutte et al., 2005). In those studies that did not use contrast agent, the main possible mechanism for the reduction of MR signal intensity in Aβ plaques was shortening of transverse relaxation time (T2) values due to the presence of iron in the plaques.
The presence of iron in Aβ plaques in postmortem human brain tissue has been previously demonstrated (LeVine, 1997; Connor et al., 1992), but there was a need for histological support of the accumulation of iron in transgenic mouse models of AD pathology. Despite the vast literature about these transgenic mice, only one study had previously demonstrated, by histochemical methods, the presence of iron in the brain (Smith et al., 1998).
In our current paper (Falangola et al., 2005), we demonstrated that iron colocalizes with Aβ plaques in the brain of the PS/APP mouse. The presence of iron in Aβ plaques in this mouse model of AD pathology confirms the source of the plaque-intrinsic MRI contrast in these animals. In particular, this work supports our hypothesis that the presence of iron in the Aβ plaques is a major factor in the signal hypointensity seen in our in vitro images (Lee et al., 2004) and in the reduction of T2 measured in vivo (Helpern et al., 2004a) in PS/APP mouse brain.
The understanding of the underlying mechanisms of the Aβ accumulation effect on quantitative MR parameters may provide important information relative to the future development and application of these techniques in humans. Actually, the presence of iron is now being exploited as an endogenous contrast agent utilizing a new MRI technique, developed by our group, called magnetic field correlation (MFC) imaging, which is designed to be contrast-sensitive to the presence of microscopic susceptibility effects (Jensen and Chandra, 2002; Helpern et al., 2004b; Ramani et al., 2005).
See also:
Ramani A, Jensen JH, Kaczynski KR, Helpern JA. In-Vivo Magnetic Field Correlation Imaging of Human Brain at 3 Tesla. Proceedings of the International Society of Magnetic Resonance in Medicine 14th Annual meeting, Miami 2005, pg 2177.
References:
Benveniste H, Einstein G, Kim KR, Hulette C, Johnson GA.
Detection of neuritic plaques in Alzheimer's disease by magnetic resonance microscopy.
Proc Natl Acad Sci U S A. 1999 Nov 23;96(24):14079-84.
PubMed.
Connor JR, Menzies SL, St Martin SM, Mufson EJ.
A histochemical study of iron, transferrin, and ferritin in Alzheimer's diseased brains.
J Neurosci Res. 1992 Jan;31(1):75-83.
PubMed.
Falangola MF, Lee SP, Nixon RA, Duff K, Helpern JA.
Histological co-localization of iron in Abeta plaques of PS/APP transgenic mice.
Neurochem Res. 2005 Feb;30(2):201-5.
PubMed.
Helpern JA, Lee SP, Falangola MF, Dyakin VV, Bogart A, Ardekani B, Duff K, Branch C, Wisniewski T, de Leon MJ, Wolf O, O'Shea J, Nixon RA.
MRI assessment of neuropathology in a transgenic mouse model of Alzheimer's disease.
Magn Reson Med. 2004 Apr;51(4):794-8.
PubMed.
Helpern JA, Jensen J, Lee SP, Falangola MF.
Quantitative MRI assessment of Alzheimer's disease.
J Mol Neurosci. 2004;24(1):45-8.
PubMed.
Jack CR, Garwood M, Wengenack TM, Borowski B, Curran GL, Lin J, Adriany G, Gröhn OH, Grimm R, Poduslo JF.
In vivo visualization of Alzheimer's amyloid plaques by magnetic resonance imaging in transgenic mice without a contrast agent.
Magn Reson Med. 2004 Dec;52(6):1263-71.
PubMed.
Jensen JH, Chandra R.
Method for Measuring the Magnetic Field Correlation Function for Water Protons in Biological Tissues.
Proc Int Soc Magn Reson Med Sci Meet. 2002;10:2297.
Lee SP, Falangola MF, Nixon RA, Duff K, Helpern JA.
Visualization of beta-amyloid plaques in a transgenic mouse model of Alzheimer's disease using MR microscopy without contrast reagents.
Magn Reson Med. 2004 Sep;52(3):538-44.
PubMed.
LeVine SM.
Iron deposits in multiple sclerosis and Alzheimer's disease brains.
Brain Res. 1997 Jun 20;760(1-2):298-303.
PubMed.
Smith MA, Hirai K, Hsiao K, Pappolla MA, Harris PL, Siedlak SL, Tabaton M, Perry G.
Amyloid-beta deposition in Alzheimer transgenic mice is associated with oxidative stress.
J Neurochem. 1998 May;70(5):2212-5.
PubMed.
Vanhoutte G, Dewachter I, Borghgraef P, Van Leuven F, Van der Linden A.
Noninvasive in vivo MRI detection of neuritic plaques associated with iron in APP[V717I] transgenic mice, a model for Alzheimer's disease.
Magn Reson Med. 2005 Mar;53(3):607-13.
PubMed.
Zhang J, Yarowsky P, Gordon MN, Di Carlo G, Munireddy S, van Zijl PC, Mori S.
Detection of amyloid plaques in mouse models of Alzheimer's disease by magnetic resonance imaging.
Magn Reson Med. 2004 Mar;51(3):452-7.
PubMed.
Wadghiri YZ, Sigurdsson EM, Sadowski M, Elliott JI, Li Y, Scholtzova H, Tang CY, Aguinaldo G, Pappolla M, Duff K, Wisniewski T, Turnbull DH.
Detection of Alzheimer's amyloid in transgenic mice using magnetic resonance microimaging.
Magn Reson Med. 2003 Aug;50(2):293-302.
PubMed.
Comments
Nathan Kline Institute
The histological demonstration of iron in Aβ plaques is important not only because of its possible role in the pathogenesis of the disease, but also because the Aβ-iron complex can be used as a mechanism of detection and progression of the disease by magnetic resonance imaging (MRI).
The detection of Alzheimer disease (AD) with noninvasive methods is a very active and important area of research. Recently, MRI has been used to detect Aβ plaques in vitro and in vivo, both with and without contrast agent (Benveniste et al., 1999; Wadghiri et al., 2003; Zhang et al., 2004; Jack et al., 2004; Lee at al., 2004; Vanhoutte et al., 2005). In those studies that did not use contrast agent, the main possible mechanism for the reduction of MR signal intensity in Aβ plaques was shortening of transverse relaxation time (T2) values due to the presence of iron in the plaques.
The presence of iron in Aβ plaques in postmortem human brain tissue has been previously demonstrated (LeVine, 1997; Connor et al., 1992), but there was a need for histological support of the accumulation of iron in transgenic mouse models of AD pathology. Despite the vast literature about these transgenic mice, only one study had previously demonstrated, by histochemical methods, the presence of iron in the brain (Smith et al., 1998).
In our current paper (Falangola et al., 2005), we demonstrated that iron colocalizes with Aβ plaques in the brain of the PS/APP mouse. The presence of iron in Aβ plaques in this mouse model of AD pathology confirms the source of the plaque-intrinsic MRI contrast in these animals. In particular, this work supports our hypothesis that the presence of iron in the Aβ plaques is a major factor in the signal hypointensity seen in our in vitro images (Lee et al., 2004) and in the reduction of T2 measured in vivo (Helpern et al., 2004a) in PS/APP mouse brain.
The understanding of the underlying mechanisms of the Aβ accumulation effect on quantitative MR parameters may provide important information relative to the future development and application of these techniques in humans. Actually, the presence of iron is now being exploited as an endogenous contrast agent utilizing a new MRI technique, developed by our group, called magnetic field correlation (MFC) imaging, which is designed to be contrast-sensitive to the presence of microscopic susceptibility effects (Jensen and Chandra, 2002; Helpern et al., 2004b; Ramani et al., 2005).
See also:
Ramani A, Jensen JH, Kaczynski KR, Helpern JA. In-Vivo Magnetic Field Correlation Imaging of Human Brain at 3 Tesla. Proceedings of the International Society of Magnetic Resonance in Medicine 14th Annual meeting, Miami 2005, pg 2177.
References:
Benveniste H, Einstein G, Kim KR, Hulette C, Johnson GA. Detection of neuritic plaques in Alzheimer's disease by magnetic resonance microscopy. Proc Natl Acad Sci U S A. 1999 Nov 23;96(24):14079-84. PubMed.
Connor JR, Menzies SL, St Martin SM, Mufson EJ. A histochemical study of iron, transferrin, and ferritin in Alzheimer's diseased brains. J Neurosci Res. 1992 Jan;31(1):75-83. PubMed.
Falangola MF, Lee SP, Nixon RA, Duff K, Helpern JA. Histological co-localization of iron in Abeta plaques of PS/APP transgenic mice. Neurochem Res. 2005 Feb;30(2):201-5. PubMed.
Helpern JA, Lee SP, Falangola MF, Dyakin VV, Bogart A, Ardekani B, Duff K, Branch C, Wisniewski T, de Leon MJ, Wolf O, O'Shea J, Nixon RA. MRI assessment of neuropathology in a transgenic mouse model of Alzheimer's disease. Magn Reson Med. 2004 Apr;51(4):794-8. PubMed.
Helpern JA, Jensen J, Lee SP, Falangola MF. Quantitative MRI assessment of Alzheimer's disease. J Mol Neurosci. 2004;24(1):45-8. PubMed.
Jack CR, Garwood M, Wengenack TM, Borowski B, Curran GL, Lin J, Adriany G, Gröhn OH, Grimm R, Poduslo JF. In vivo visualization of Alzheimer's amyloid plaques by magnetic resonance imaging in transgenic mice without a contrast agent. Magn Reson Med. 2004 Dec;52(6):1263-71. PubMed.
Jensen JH, Chandra R. Method for Measuring the Magnetic Field Correlation Function for Water Protons in Biological Tissues. Proc Int Soc Magn Reson Med Sci Meet. 2002;10:2297.
Lee SP, Falangola MF, Nixon RA, Duff K, Helpern JA. Visualization of beta-amyloid plaques in a transgenic mouse model of Alzheimer's disease using MR microscopy without contrast reagents. Magn Reson Med. 2004 Sep;52(3):538-44. PubMed.
LeVine SM. Iron deposits in multiple sclerosis and Alzheimer's disease brains. Brain Res. 1997 Jun 20;760(1-2):298-303. PubMed.
Smith MA, Hirai K, Hsiao K, Pappolla MA, Harris PL, Siedlak SL, Tabaton M, Perry G. Amyloid-beta deposition in Alzheimer transgenic mice is associated with oxidative stress. J Neurochem. 1998 May;70(5):2212-5. PubMed.
Vanhoutte G, Dewachter I, Borghgraef P, Van Leuven F, Van der Linden A. Noninvasive in vivo MRI detection of neuritic plaques associated with iron in APP[V717I] transgenic mice, a model for Alzheimer's disease. Magn Reson Med. 2005 Mar;53(3):607-13. PubMed.
Zhang J, Yarowsky P, Gordon MN, Di Carlo G, Munireddy S, van Zijl PC, Mori S. Detection of amyloid plaques in mouse models of Alzheimer's disease by magnetic resonance imaging. Magn Reson Med. 2004 Mar;51(3):452-7. PubMed.
Wadghiri YZ, Sigurdsson EM, Sadowski M, Elliott JI, Li Y, Scholtzova H, Tang CY, Aguinaldo G, Pappolla M, Duff K, Wisniewski T, Turnbull DH. Detection of Alzheimer's amyloid in transgenic mice using magnetic resonance microimaging. Magn Reson Med. 2003 Aug;50(2):293-302. PubMed.
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