Application of QSM in the Brain: Neurodegenerative
Minming Zhang

Synopsis

Iron measured by MRI in vivo would contribute to searching for iron-related biomarkers in neurodegenerative diseases, like Parkinson's disease.

Here, we would like to briefly introduce the technological development of MRI in assessing brain iron, discuss the nigral iron as a potential marker for PD in both clinical and prodromal stages, further put insight into other influences of regional iron on PD symptoms.

Abstract

Iron plays an essential role in physiological function during normal aging, including oxygen transportation, DNA synthesis and repair, mitochondrial respiration, myelin synthesis, neurotransmitter synthesis and metabolism(1). Dysfunction of iron homoeostasis can contribute to the generation of free radicals, leading to the oxidation of proteins, lipids, lipoproteins and other cellular components, which can result in neuronal death (1, 2, 3). Pathological iron accumulation was widely observed in the neurodegenerative diseases by histochemical studies, such as Parkinson’s disease (PD) in the substantia nigra (4, 5, 6). However, those studies cannot provide in vivo measurement of regional iron neither the interaction between iron and clinical expressions. To prompt the clinical investigation, magnetic resonance imaging (MRI), especially the most advanced technique – quantitative susceptibility mapping (QSM), has been developed to evaluate brain iron content in vivo. In past decades, field-dependent methods (7, 8), T2* mapping (9), T2′ mapping (10, 11), phase imaging (12, 13) and QSM (14, 15, 16) for detecting iron content in healthy controls have been highly consistent with postmortem results. Therefore, we would like to explain the application of regional iron measured by MRI in the neurodegenerative brains. PD is one of the most common neurodegenerative diseases and has heterogeneous clinical symptoms(17, 18). The diagnosis of PD mainly depends on the occurrence of motor impairments, such as akinesia, rigidity and resting tremor, which lacks objective evidence (18, 19). Significant motor symptoms generally emerge only after 50–70% of the dopaminergic neurons are irreversibly lost in the substantia nigra pars compacta (SNc) (20, 21), which indicates a pathologically advanced stage (22, 23). In clinical practice, there are no sensitive and specific biomarkers for PD. Therefore, misdiagnosis is high, ranging from 12% to 74%, where patients with a shorter disease duration or without a clear response to dopaminergic medication having markedly higher rates of misdiagnosis (24). Previous studies indicate little improvement in the diagnostic accuracy of PD over the past 20 years(24, 25), indicating an urgent need for a clinical biomarker to aid diagnosis. Here, we will take PD as an example and try to briefly introduce the technological development of MRI in assessing brain iron, discuss the nigral iron as a potential marker for PD in both clinical and prodromal stages, further put insight into other influences of regional iron on PD symptoms.

Acknowledgements

This work was supported by the 13th Five-year Plan for National Key Research and Development Program of China (Grant No. 2016YFC1306600), the 12th Five-year Plan for National Science and Technology Supporting Program of China (Grant No. 2012BAI10B04) and the National Natural Science Foundation of China (Grant Nos. 81571654, 81371519 and 81301190).

References

[1] R.J. Ward, F.A. Zucca, J.H. Duyn, R.R. Crichton, and L. Zecca, The role of iron in brain ageing and neurodegenerative disorders. Lancet Neurol 2014;13:1045-60.

[2] R.J. Ward, D.T. Dexter, and R.R. Crichton, Neurodegenerative diseases and therapeutic strategies using iron chelators. J Trace Elem Med Biol 2015;31:267-273.

[3] J.A. Gaasch, P.R. Lockman, W.J. Geldenhuys, D.D. Allen, and C.J. Van der Schyf, Brain iron toxicity: differential responses of astrocytes, neurons, and endothelial cells. Neurochem Res 2007;32:1196-208.

[4] E. Sofic, P. Riederer, H. Heinsen, H. Beckmann, G.P. Reynolds, G. Hebenstreit, and M.B. Youdim, Increased iron (III) and total iron content in post mortem substantia nigra of parkinsonian brain. J Neural Transm 1988;74:199-205.

[5] D.T. Dexter, F.R. Wells, F. Agid, Y. Agid, A.J. Lees, P. Jenner, and C.D. Marsden, Increased nigral iron content in postmortem parkinsonian brain. Lancet 1987;2:1219-20.

[6] E. Sofic, W. Paulus, K. Jellinger, P. Riederer, and M.B. Youdim, Selective increase of iron in substantia nigra zona compacta of parkinsonian brains. J Neurochem 1991;56:978-82.

[7] G. Bartzokis, M. Beckson, D.B. Hance, P. Marx, J.A. Foster, and S.R. Marder, MR evaluation of age-related increase of brain iron in young adult and older normal males. Magn Reson Imaging 1997;15:29-35.

[8] G. Bartzokis, J. Mintz, D. Sultzer, P. Marx, J.S. Herzberg, C.K. Phelan, and S.R. Marder, In vivo MR evaluation of age-related increases in brain iron. AJNR Am J Neuroradiol 1994;15:1129-38.

[9] C. Langkammer, N. Krebs, W. Goessler, E. Scheurer, F. Ebner, K. Yen, F. Fazekas, and S. Ropele, Quantitative MR imaging of brain iron: a postmortem validation study. Radiology 2010;257:455-62.

[10] Y. Qin, W. Zhu, C. Zhan, L. Zhao, J. Wang, Q. Tian, and W. Wang, Investigation on positive correlation of increased brain iron deposition with cognitive impairment in Alzheimer disease by using quantitative MR R2' mapping. J Huazhong Univ Sci Technolog Med Sci 2011;31:578-85.

[11] N. Gelman, J.M. Gorell, P.B. Barker, R.M. Savage, E.M. Spickler, J.P. Windham, and R.A. Knight, MR imaging of human brain at 3.0 T: preliminary report on transverse relaxation rates and relation to estimated iron content. Radiology 1999;210:759-67.

[12] W.Z. Zhu, W.D. Zhong, W. Wang, C.J. Zhan, C.Y. Wang, J.P. Qi, J.Z. Wang, and T. Lei, Quantitative MR phase-corrected imaging to investigate increased brain iron deposition of patients with Alzheimer disease. Radiology 2009;253:497-504.

[13] X. Xu, Q. Wang, and M. Zhang, Age, gender, and hemispheric differences in iron deposition in the human brain: an in vivo MRI study. Neuroimage 2008;40:35-42.

[14] C. Langkammer, F. Schweser, N. Krebs, A. Deistung, W. Goessler, E. Scheurer, K. Sommer, G. Reishofer, K. Yen, F. Fazekas, S. Ropele, and J.R. Reichenbach, Quantitative susceptibility mapping (QSM) as a means to measure brain iron? A post mortem validation study. Neuroimage 2012;62:1593-9.

[15] W. Li, B. Wu, A. Batrachenko, V. Bancroft-Wu, R.A. Morey, V. Shashi, C. Langkammer, M.D. De Bellis, S. Ropele, A.W. Song, and C. Liu, Differential developmental trajectories of magnetic susceptibility in human brain gray and white matter over the lifespan. Hum Brain Mapp 2014;35:2698-713.

[16] B. Wu, W. Li, A. Guidon, and C. Liu, Whole brain susceptibility mapping using compressed sensing. Magn Reson Med 2012;67:137-47.

[17] J. Jankovic, M. McDermott, J. Carter, S. Gauthier, C. Goetz, L. Golbe, S. Huber, W. Koller, C. Olanow, I. Shoulson, and A. Et, Variable expression of Parkinson's disease: a base-line analysis of the DATATOP cohort. The Parkinson Study Group. Neurology 1990;40:1529-34.

[18] A.J. Lees, J. Hardy, and T. Revesz, Parkinson's disease. LANCET 2009;373:2055-2066.

[19] A.J. Hughes, S.E. Daniel, L. Kilford, and A.J. Lees, Accuracy of clinical diagnosis of idiopathic Parkinson's disease: a clinico-pathological study of 100 cases. J Neurol Neurosurg Psychiatry 1992;55:181-4.

[20] P. Damier, E.C. Hirsch, Y. Agid, and A.M. Graybiel, The substantia nigra of the human brain. II. Patterns of loss of dopamine-containing neurons in Parkinson's disease. Brain 1999;122 ( Pt 8):1437-48. [21] J.M. Fearnley, and A.J. Lees, Ageing and Parkinson's disease: substantia nigra regional selectivity. Brain 1991;114 ( Pt 5):2283-301.

[22] H. Braak, E. Ghebremedhin, U. Rub, H. Bratzke, and T.K. Del, Stages in the development of Parkinson's disease-related pathology. Cell Tissue Res 2004;318:121-34.

[23] H. Braak, T.K. Del, U. Rub, R.A. de Vos, S.E. Jansen, and E. Braak, Staging of brain pathology related to sporadic Parkinson's disease. Neurobiol Aging 2003;24:197-211.

[24] C.H. Adler, T.G. Beach, J.G. Hentz, H.A. Shill, J.N. Caviness, E. Driver-Dunckley, M.N. Sabbagh, L.I. Sue, S.A. Jacobson, C.M. Belden, and B.N. Dugger, Low clinical diagnostic accuracy of early vs advanced Parkinson disease: clinicopathologic study. Neurology 2014;83:406-12.

[25] A.H. Rajput, B. Rozdilsky, and A. Rajput, Accuracy of clinical diagnosis in parkinsonism--a prospective study. Can J Neurol Sci 1991;18:275-8.

Proc. Intl. Soc. Mag. Reson. Med. 25 (2017)