Investigation on positive correlation of increased brain iron deposition with cognitive impairment in Alzheimer disease by using quantitative MR R2′ mapping

Abstract

Brain iron deposition has been proposed to play an important role in the pathophysiology of Alzheimer disease (AD). The aim of this study was to investigate the correlation of brain iron accumulation with the severity of cognitive impairment in patients with AD by using quantitative MR relaxation rate R2′ measurements. Fifteen patients with AD, 15 age- and sex-matched healthy controls, and 30 healthy volunteers underwent 1.5T MR multi-echo T2 mapping and T2* mapping for the measurement of transverse relaxation rate R2′ (R2′=R2*−R2). We statistically analyzed the R2′ and iron concentrations of bilateral hippocampus (HP), parietal cortex (PC), frontal white matter (FWM), putamen (PU), caudate nucleus (CN), thalamus (TH), red nucleus (RN), substantia nigra (SN), and dentate nucleus (DN) of the cerebellum for the correlation with the severity of dementia. Two-tailed t-test, Student-Newman-Keuls test (ANOVA) and linear correlation test were used for statistical analysis. In 30 healthy volunteers, the R2′ values of bilateral SN, RN, PU, CN, globus pallidus (GP), TH, and FWM were measured. The correlation with the postmortem iron concentration in normal adults was analyzed in order to establish a formula on the relationship between regional R2′ and brain iron concentration. The iron concentration of regions of interest (ROI) in AD patients and controls was calculated by this formula and its correlation with the severity of AD was analyzed. Regional R2′ was positively correlated with regional brain iron concentration in normal adults (r=0.977, P<0.01). Iron concentrations in bilateral HP, PC, PU, CN, and DN of patients with AD were significantly higher than those of the controls (P<0.05); Moreover, the brain iron concentrations, especially in parietal cortex and hippocampus at the early stage of AD, were positively correlated with the severity of patients’ cognitive impairment (P<0.05). The higher the R2′ and iron concentrations were, the more severe the cognitive impairment was. Regional R2′ and iron concentration in parietal cortex and hippocampus were positively correlated with the severity of AD patients’ cognitive impairment, indicating that it may be used as a biomarker to evaluate the progression of AD.

Keywords

Alzheimer disease / iron deposition / quantitative magnetic resonance imaging / transverse relaxation rate R2′ / imaging marker

References

[1] LovellM.A., RobertsonJ.D., TeesdaleW.J., et al.. Copper, iron and zinc in Alzheimer’s disease senile plaques. J Neurol Sci, 1998, 158(1): 47-52

[2] BishopG.M., RobinsonS.R., LiuQ., et al.. Iron: a pathological mediator of Alzheimer disease?. Dev Neurosci, 2002, 24(2–3): 184-187

[3] ZeccaL., YoudimM.B., RiedererP., et al.. Iron, brain ageing and neurodegenerative disorders. Nat Rev Neurosci, 2004, 5(11): 863-873

[4] HondaK., CasadesusG., PetersenR.B., et al.. Oxidative stress and redoxactive iron in Alzheimer’s disease. Ann N Y Acad Sci, 2004, 1012: 179-182

[5] SmithM.A., HarrisP.L.R., SayreL.M., et al.. Iron accumulation in Alzheimer disease is a source of redox-generated free radicals. Proc Natl Acad Sci USA, 1997, 94(18): 9866-9868

[6] RottkampC.A., RainaA.K., ZhuX., et al.. Redox-active iron mediates amyloid-beta toxicity. Free Radic Biol Med, 2001, 30(4): 447-450

[7] CasadesusG., SmithM.A., ZhuX., et al.. Alzheimer disease: evidence for a central pathogenic role of iron-mediated reactive oxygen species. J Alzheimers Dis, 2004, 6(2): 165-169

[8] HaackeE.M., XuY., ChengY.C., et al.. Susceptibility weighted imaging (SWI). Magn Reson Med, 2004, 52(3): 612-618

[9] ZhuW.Z., ZhongW.D., WangW., et al.. Quantitative MR phase-corrected imaging to investigate increased brain iron deposition of patients with Alzheimer Disease. Radiology, 2009, 253(2): 497-504

[10] OrdidgeR.J., GorellJ.M., DeniauJ.C., et al.. Assessment of relative brain iron concentrations using T2-weighted and T2*-weighted MRI at 3 Tesla. Magn Reson Med, 1994, 32(3): 335-341

[11] BrooksR.A., VymazalJ., GoldfarbR.B., et al.. Relaxometry and magnetometry of ferritin. Magn Reson Med, 1998, 40(2): 227-235

[12] GelmanN., GorellJ.M., BarkerP.B., et al.. MR imaging of human brain at 3. 0 T: preliminary report on transverse relaxation rates and relation to estimated iron content. Radiology, 1999, 210(3): 759-767

[13] BartzokisG., TishlerT.A.. MRI evaluation of basal ganglia ferritin iron and neurotoxicity in Alzheimer’s and Huntington’s disease. Cell Mol Biol (Noisy-le-grand), 2000, 46(4): 821-833

[14] ZywickeH.A., Van GelderenP., ConnorJ.R.. Microscopic R2* mapping of reduced brain iron in the Belgrade rat. Ann Neurol, 2002, 52(1): 102-105

[15] HardyP.A., GashD., YokelR., et al.. Correlation of R2 with total iron concentration in the brains of rhesus monkeys. J Magn Reson Imaging, 2005, 21(2): 118-127

[16] HikitaT., KazuoA., SakodaS., et al.. Determination of transverse relaxation rate for estimating iron deposits in the central nervous system. Neurosci Res, 2005, 51(1): 67-71

[17] JaraH., SakaiO., MankalP., et al.. Multispectral quantitative magnetic resonance imaging of brain iron stores: A theoretical perspective. Top Magn Reson Imaging, 2006, 17(1): 19-30

[18] BrassS.D., ChenT., MulkernR.V., et al.. Magnetic resonance imaging of iron deposition in neurological disorders. Top Magn Reson Imaging, 2006, 17(1): 31-40

[19] AnH., LinW.. Quantitative measurements of cerebral blood oxygen saturation using magnetic resonance imaging. J Cereb Blood Flow Metab, 2000, 20(8): 1225-1236

[20] WallisL.I., PaleyM.N.J., GrahamJ.M., et al.. MRI assessment of basal ganglia iron deposition in Parkinson’s disease. J Magn Reson Imaging, 2008, 28(5): 1061-1067

[21] HallgrenB., SouranderP.. The effect of age on the non-haemin iron in the human brain. J Neurochem, 1958, 3(1): 41-51

[22] McKhannG., DrachmanD., FolsteinM., et al.. Clinical diagnosis of Alzheimer’s disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology, 1984, 34(7): 939-944

[23] SchenckJ.F., ZimmermanE.A.. High-field magnetic resonance imaging of brain iron: birth of a biomarker?. NMR Biomed, 2004, 17(7): 433-445

[24] PankhurstQ., HautotD., KhanN., et al.. Increased levels of magnetic iron compounds in Alzheimer’s disease. J Alzheimers Dis, 2008, 13(1): 49-52

[25] ThompsonC.M., MarkesberyW.R., EhmannW.D., et al.. Regional brain trace element studies in Alzheimer’s disease. Neurotoxicology, 1988, 9(1): 1-8

[26] DeibelM.A., EhmannW.D., MarkesberyW.D.. Copper, iron, and zinc imbalances in severely degenerated brain regions in Alzheimer’s disease: possible relation to oxidative stress. J Neurol Sci, 1996, 143(1–2): 137-142

[27] CornettC.R., MarkesberyW.R., EhmannW.D.. Imbalances of trace elements related to oxidative damage in Alzheimer’s disease brain. Neurotoxicology, 1998, 19(3): 339-345

[28] BorthakurA., GurT., WheatonA.J., et al.. In vivo measurement of plaque burden in a mouse model of Alzheimer’s disease. J Magn Reson Imaging, 2006, 24(5): 1011-1017

[29] NakadaT., MatsuzawaH., IgarashiH., et al.. In vivo visualization of senile-plaque-like pathology in Alzheimer’s disease patients by MR microscopy on a 7T system. J Neuroimaging, 2008, 18(2): 125-129

[30] SmithM.A., WehrK., HarrisP. A., et al.. bnormal localization of iron regulatory protein in Alzheimer’s disease. Brain Res, 1998, 788(1–2): 232-236

[31] GrabillC., SilvaA.C., SmithS.S., et al.. MRI detection of ferritin iron overload and associated neuronal pathology in iron regulatory protein-2 knockout mice. Brain Res, 2003, 971(1): 95-106

[32] WengenackT.M., JackC.R.Jr, GarwoodM., et al.. MR microimaging of amyloid plaques in Alzheimer’s disease transgenic mice. Eur J Nucl Med Mol Imaging, 2008, 35(Suppl1): S82-88

[33] BartzokisG., TishlerT.A., ShinI.S., et al.. Brain ferritin iron as a risk factor for age at onset in neurodegenerative diseases. Ann N Y Acad Sci, 2004, 1012: 224-236

[34] HouseM.J., St PierreT.G., FosterJ.K., et al.. Quantitative MR imaging R2 relaxometry in elderly participants reporting memory loss. Am J Neuroradiol, 2006, 27(2): 430-439