Huntington's disease (HD) is an inherited neurodegenerative disorder with progressive impairment of motor, behavioral and cognitive functions. The clinical features of HD are closely related to the degeneration of the basal ganglia, predominantly the striatum. The main striatal output structure, the globus pallidus, strongly accumulates metalloprotein-bound iron, which was recently shown to influence the diffusion tensor scalar values. To test the hypothesis that this effect dominates in the iron-rich basal ganglia of HD patients, we examined the globus pallidus using DTI and T2 relaxometry sequences. Quantitative magnetic resonance (MR), clinical and genetic data (number of CAG repeats) were obtained from 14 HD patients. MR parameters such as the T2 relaxation rate (RR), fractional anisotropy (FA) and mean diffusivity (MD) were analysed. A positive correlation was found between RR and FA (R2=0.84), between CAG and RR (R2=0.59) and between CAG and FA (R2=0.44). A negative correlation was observed between RR and MD (R2=0.66). A trend towards correlation between CAG and MD was noted. No correlation between MR and clinical parameters was found. Our results indicate that especially magnetic resonance FA measurements in the globus pallidus of HD patients may be strongly affected by metalloprotein-bound iron accumulation.

Department of Neurology and Center of Clinical Neuroscience 1st Faculty of Medicine and General University Hospital Prague Charles University Prague Prague Czech Republic

Department of Neurology and Center of Clinical Neuroscience 1st Faculty of Medicine and General University Hospital Prague Charles University Prague Prague Czech Republic; Institute of Anatomy 1st Faculty of Medicine Charles University Prague Prague Czech Republic

Department of Radiology Na Homolce Hospital Prague Czech Republic

Department of Radiology Na Homolce Hospital Prague Czech Republic; Department of Neurology 3rd Faculty of Medicine Charles University Prague Prague Czech Republic

Department of Radiology Na Homolce Hospital Prague Czech Republic; Department of Radiology 1st Faculty of Medicine and General University Hospital Prague Charles University Prague Prague Czech Republic

Department of Radiology Na Homolce Hospital Prague Czech Republic; International Clinical Research Center St Anne´s University Hospital Brno Czech Republic; Institute of Experimental Medicine Academy of Sciences of the Czech Republic v v i Prague Czech Republic

Institute of Experimental Medicine Academy of Sciences of the Czech Republic v v i Prague Czech Republic

See more in PubMed

Gusella JF, Wexler NS, Conneally PM, Naylor SL, Anderson MA, Tanzi RE, et al. A polymorphic DNA marker genetically linked to Huntington's disease. Nature. 1983;306: 234–8. PubMed

A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes. The Huntington's Disease Collaborative Research Group. Cell. 1993;72: 971–83. PubMed

Gusella JF, MacDonald ME. Huntingtin: a single bait hooks many species. Curr Opin Neurobiol. 1998;8: 425–30. PubMed

Cattaneo E, Rigamonti D, Goffredo D, Zuccato C, Squitieri F, Sipione S. Loss of normal huntingtin function: new developments in Huntington's disease research. Trends Neurosci. 2001;24: 182–8. PubMed

Albin RL. Selective neurodegeneration in Huntington's disease. Ann Neurol. 1995;38: 835–6. PubMed

Vonsattel JP, DiFiglia M. Huntington disease. J Neuropathol Exp Neurol. 1998;57: 369–84. PubMed

Vonsattel JP, Myers RH, Stevens TJ, Ferrante RJ, Bird ED, Richardson EP Jr. Neuropathological classification of Huntington's disease. J Neuropathol Exp Neurol. 1985;44: 559–77. PubMed

Rosas HD, Koroshetz WJ, Chen YI, Skeuse C, Vangel M, Cudkowicz ME, et al. Evidence for more widespread cerebral pathology in early HD: an MRI-based morphometric analysis. Neurology. 2003;60: 1615–20. PubMed

Unified Huntington's Disease Rating Scale: reliability and consistency. Huntington Study Group. Mov Disord. 1996;11: 136–42. PubMed

Mascalchi M, Lolli F, Della Nave R, Tessa C, Petralli R, Gavazzi C, et al. Huntington disease: volumetric, diffusion-weighted, and magnetization transfer MR imaging of brain. Radiology. 2004;232: 867–73. PubMed

Rosas HD, Tuch DS, Hevelone ND, Zaleta AK, Vangel M, Hersch SM, et al. Diffusion tensor imaging in presymptomatic and early Huntington’s disease: Selective white matter pathology and its relationship to clinical measures. Mov Disord. 2006;21: 1317–25. PubMed

Douaud G, Behrens TE, Poupon C, Cointepas Y, Jbabdi S, Gaura V, et al. In vivo evidence for the selective subcortical degeneration in Huntington’s disease. NeuroImage. 2009;46: 958–66. 10.1016/j.neuroimage.2009.03.044 PubMed DOI

Seppi K, Schocke MF, Mair KJ, Esterhammer R, Weirich-Schwaiger H, Utermann B, et al. Diffusion-weighted imaging in Huntington's disease. Mov Disord. 2006;21: 1043–7. PubMed

Sánchez-Castañeda C, Cherubini A, Elifani F, Péran P, Orobello S, Capelli G, et al. Seeking huntington disease biomarkers by multimodal, cross-sectional basal ganglia imaging. Hum Brain Mapp. 2013;34: 1625–35. 10.1002/hbm.22019 PubMed DOI PMC

Pierpaoli C, Jezzard P, Basser PJ, Barnett A, Di Chiro G. Diffusion tensor MR imaging of the human brain. Radiology. 1996;201: 637–48. PubMed

Hasan KM, Halphen C, Kamali A, Nelson FM, Wolinsky JS, Narayana PA. Caudate nuclei volume, diffusion tensor metrics, and T2 relaxation in healthy adults and relapsing-remitting multiple sclerosis patients: Implications to understanding gray matter degeneration. J Magn Reson Imaging. 2009;29: 70–77. 10.1002/jmri.21648 PubMed DOI PMC

Drayer B, Burger P, Darwin R, Riederer S, Herfkens R, Johnson GA. MRI of brain iron. Am J Roentgenol. 1986;147: 103–10. PubMed

Schenker C, Meier D, Wichmann W, Boesiger P, Valavanis A. Age distribution and iron dependency of the T2 relaxation time in the globus pallidus and putamen. Neuroradiology. 1993;35: 119–24. PubMed

Bartzokis G, Aravagiri M, Oldendorf WH, Mintz J, Marder SR. Field dependent transverse relaxation rate increase may be a specific measure of tissue iron stores. Magn Reson Med. 1993;29: 459–64. PubMed

Vymazal J, Hajek M, Patronas N, Giedd JN, Bulte JW, Baumgarner C, et al. The quantitative relation between T1-weighted and T2-weighted MRI of normal gray matter and iron concentration. J Magn Reson Imaging. 1995;5: 554–60. PubMed

Hallgren B, Sourander P. The effect of age on the non-haemin iron in the human brain. J Neurochem. 1958;3: 41–51. PubMed

Aquino D, Bizzi A, Grisoli M, Garavaglia B, Bruzzone MG, Nardocci N, et al. Age-related iron deposition in the basal ganglia: quantitative analysis in healthy subjects. Radiology. 2009;252: 165–72. 10.1148/radiol.2522081399 PubMed DOI

Péran P, Cherubini A, Luccichenti G, Hagberg G, Démonet JF, Rascol O, et al. Volume and iron content in basal ganglia and thalamus. Hum Brain Mapp. 2009;30: 2667–75. 10.1002/hbm.20698 PubMed DOI PMC

Bartzokis G, Mintz J, Sultzer D, Marx P, Herzberg JS, Phelan CK, et al. In vivo MR evaluation of age-related increases in brain iron. Am J Neuroradiol.1994;15: 1129–38. PubMed PMC

Vymazal J, Righini A, Brooks RA, Canesi M, Mariani C, Leonardi M, et al. T1 and T2 in the brain of healthy subjects, patients with Parkinson disease, and patients with multiple system atrophy: relation to iron content. Radiology. 1999;211: 489–95. PubMed

Hájek M, Adamovicová M, Herynek V, Skoch A, Jírů F, Krepelová A, et al. MR relaxometry and 1H MR spectroscopy for the determination of iron and metabolite concentrations in PKAN patients. Eur Radiol. 2005;15: 1060–8. PubMed

Bartzokis G, Tishler TA. MRI evaluation of basal ganglia ferritin iron and neurotoxicity in Alzheimer's and Huntingon's disease. Cell Mol Biol. 2000;46: 821–33. PubMed

Zecca L, Youdim MBH, Riederer P, Connor JR, Crichton RR. Iron, brain aging and neurodegenerative disorders. Nat Rev Neurosci. 2004;5: 863–73. PubMed

Bartzokis G, Cummings J, Perlman S, Hance DB, Mintz J. Increased basal ganglia iron levels in Huntington disease. Arch Neurol. 1999;56: 569–74. PubMed

Vymazal J, Klempíř J, Jech R, Židovská J, Syka M, Růžička E, et al. MR relaxometry in Huntington’s disease: correlation between imaging, genetic and clinical parameters. J Neurol Sci. 2007;263: 20–25. PubMed

Rosas HD, Chen YI, Doros G, Salat DH, Chen NK, Kwong KK, et al. Alterations in brain transition metals in Huntington disease: an evolving and intricate story. Arch Neurol. 2012;69: 887–93. PubMed PMC

McGahan MC, Harned J, Mukunnemkeril M, Goralska M, Fleisher L, Ferrell JB. Iron alters glutamate secretion by regulating cytosolic aconitase activity. Am J Physiol Cell Physiol. 2005;288: 1117–24. PubMed

Bartzokis G, Lu PH, Tishler TA, Fong SM, Oluwadara B, Finn JP, et al. Myelin breakdown and iron changes in Huntington's disease: pathogenesis and treatment implications. Neurochem Res. 2007;32: 1655–64. PubMed

Pfefferbaum A, Adalsteinsson E, Rohlfing T, Sullivan EV. Diffusion tensor imaging of deep gray matter brain structures: Effects of age and iron concentration. Neurobiol Aging. 2010;31: 482–93. 10.1016/j.neurobiolaging.2008.04.013 PubMed DOI PMC

Rulseh AM, Keller J, Tintěra J, Kožíšek M, Vymazal J. Chasing shadows: What determines DTI metrics in gray matter regions? An in vitro and in vivo study. J Magn Reson Imaging. 2013;38: 1103–10. 10.1002/jmri.24065 PubMed DOI

Walimuni IS, Hasan KM. Atlas-based investigation of human brain tissue microstructural spatial heterogeneity and interplay between transverse relaxation time and radial diffusivity. Neuroimage. 2011;57: 1402–10. 10.1016/j.neuroimage.2011.05.063 PubMed DOI PMC

Warner JP, Barron LH, Brock DJ. A new polymerase chain reaction (PCR) assay for the trinucleotide repeat that is unstable and expanded on Huntington's disease chromosomes. Mol Cell Probes. 1993;7: 235–9. PubMed

Penney JB Jr., Vonsattel JP, MacDonald ME, Gusella JF, Myers RH. CAG repeat number governs the development rate of pathology in Huntington's disease. Annals of Neurology. 1997;41: 689–92. PubMed

Smith SM, Jenkinson M, Woolrich MW, Beckmann CF, Behrens TEJ, Johansen-Berg H, et al. Advances in functional and structural MR image analysis and implementation as FSL. NeuroImage. 2004;1: 208–19. PubMed

Smith SM. Fast robust automated brain extraction. Hum Brain Mapp. 2002;17: 143–55. PubMed PMC

Pierpaoli C, Basser PJ. Toward a quantitative assessment of diffusion anisotropy. Magn Reson Med; 1996;36: 893–906. PubMed

Bastin ME, Armitage PA, Marshall I. A theoretical study of the effect of experimental noise on the measurement of anisotropy in diffusion imaging. Magn Reson Imaging. 1998;16: 773–85. PubMed

Chen JC, Hardy PA, Kucharczyk W, Clauberg M, Joshi JG, Vourlas A, et al. MR of human postmortem brain tissue: correlative study between T2 and assays of iron and ferritin in Parkinson and Huntington disease. Am J Neuroradiol. 1993;14: 275–81. PubMed PMC

Vorisek I, Sykova E. Measuring diffusion parameters in the brain: comparing the real-time iontophoretic method and diffusion-weighted magnetic resonance. Acta Physiol (Oxf). 2009;195: 101–10. 10.1111/j.1748-1716.2008.01924.x PubMed DOI

Herynek V, Wagnerová D, Hejlová I, Dezortová M, Hájek M. Changes in the Brain During Long-Term Follow-up After Liver Transplantation. Magn Reson Imaging. 2012;35: 1332–7. 10.1002/jmri.23599 PubMed DOI

Dezortova M, Herynek V, Krssak M, Kronerwetter C, Trattnig S, Hajek M. Two forms of iron as an intrinsic contrast agent in the basal ganglia of PKAN patients. Contrast Media Mol Imaging. 2012;7: 509–15. 10.1002/cmmi.1482 PubMed DOI

Ordidge RJ, Gorell JM, Deniau JC, Knight RA, Helpern JA. Assessment of relative brain iron concentrations using T2-weighted and T2*-weighted MRI at 3 Tesla. Magn Reson Med. 1994;32: 335–41. PubMed