Iron accumulation in deep cortical layers accounts for MRI signal abnormalities in ALS: correlating 7 tesla MRI and pathology
Justin Y Kwan, Suh Young Jeong, Peter Van Gelderen, Han-Xiang Deng, Martha M Quezado, Laura E Danielian, John A Butman, Lingye Chen, Elham Bayat, James Russell, Teepu Siddique, Jeff H Duyn, Tracey A Rouault, Mary Kay Floeter, Justin Y Kwan, Suh Young Jeong, Peter Van Gelderen, Han-Xiang Deng, Martha M Quezado, Laura E Danielian, John A Butman, Lingye Chen, Elham Bayat, James Russell, Teepu Siddique, Jeff H Duyn, Tracey A Rouault, Mary Kay Floeter
Abstract
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by cortical and spinal motor neuron dysfunction. Routine magnetic resonance imaging (MRI) studies have previously shown hypointense signal in the motor cortex on T(2)-weighted images in some ALS patients, however, the cause of this finding is unknown. To investigate the utility of this MR signal change as a marker of cortical motor neuron degeneration, signal abnormalities on 3T and 7T MR images of the brain were compared, and pathology was obtained in two ALS patients to determine the origin of the motor cortex hypointensity. Nineteen patients with clinically probable or definite ALS by El Escorial criteria and 19 healthy controls underwent 3T MRI. A 7T MRI scan was carried out on five ALS patients who had motor cortex hypointensity on the 3T FLAIR sequence and on three healthy controls. Postmortem 7T MRI of the brain was performed in one ALS patient and histological studies of the brains and spinal cords were obtained post-mortem in two patients. The motor cortex hypointensity on 3T FLAIR images was present in greater frequency in ALS patients. Increased hypointensity correlated with greater severity of upper motor neuron impairment. Analysis of 7T T(2)(*)-weighted gradient echo imaging localized the signal alteration to the deeper layers of the motor cortex in both ALS patients. Pathological studies showed increased iron accumulation in microglial cells in areas corresponding to the location of the signal changes on the 3T and 7T MRI of the motor cortex. These findings indicate that the motor cortex hypointensity on 3T MRI FLAIR images in ALS is due to increased iron accumulation by microglia.
Trial registration: ClinicalTrials.gov NCT00334516.
Conflict of interest statement
Competing Interests: The authors have declared that no competing interests exist.
Figures
References
- Ince PG, Evans J, Knopp M, Forster G, Hamdalla HH, et al. Corticospinal tract degeneration in the progressive muscular atrophy variant of ALS. Neurology. 2003;60:1252–1258.
- Ellis CM, Simmons A, Jones DK, Bland J, Dawson JM, et al. Diffusion tensor MRI assesses corticospinal tract damage in ALS. Neurology. 1999;53:1051–1058.
- Mitsumoto H, Ulug AM, Pullman SL, Gooch CL, Chan S, et al. Quantitative objective markers for upper and lower motor neuron dysfunction in ALS. Neurology. 2007;68:1402–1410.
- Iwata NK, Kwan JY, Danielian LE, Butman JA, Tovar-Moll F, et al. White matter alterations differ in primary lateral sclerosis and amyotrophic lateral sclerosis. Brain. 2011;134:2642–2655.
- Hecht MJ, Fellner F, Fellner C, Hilz MJ, Neundorfer B, et al. Hyperintense and hypointense MRI signals of the precentral gyrus and corticospinal tract in ALS: a follow-up examination including FLAIR images. J Neurol Sci. 2002;199:59–65.
- Bowen BC, Pattany PM, Bradley WG, Murdoch JB, Rotta F, et al. MR imaging and localized proton spectroscopy of the precentral gyrus in amyotrophic lateral sclerosis. AJNR Am J Neuroradiol. 2000;21:647–658.
- Miwa H, Kajimoto Y, Nakanishi I, Morita S, Komoto J, et al. T2-low signal intensity in the cortex in multiple system atrophy. J Neurol Sci. 2003;211:85–88.
- Ngai S, Tang YM, Du L, Stuckey S. Hyperintensity of the precentral gyral subcortical white matter and hypointensity of the precentral gyrus on fluid-attenuated inversion recovery: variation with age and implications for the diagnosis of amyotrophic lateral sclerosis. AJNR Am J Neuroradiol. 2007;28:250–254.
- Imon Y, Yamaguchi S, Yamamura Y, Tsuji S, Kajima T, et al. Low intensity areas observed on T2-weighted magnetic resonance imaging of the cerebral cortex in various neurological diseases. J Neurol Sci. 1995;134(Suppl):27–32.
- Oba H, Araki T, Ohtomo K, Monzawa S, Uchiyama G, et al. Amyotrophic lateral sclerosis: T2 shortening in motor cortex at MR imaging. Radiology. 1993;189:843–846.
- Hecht MJ, Fellner C, Schmid A, Neundorfer B, Fellner FA. Cortical T2 signal shortening in amyotrophic lateral sclerosis is not due to iron deposits. Neuroradiology. 2005;47:805–808.
- Zecca L, Youdim MB, Riederer P, Connor JR, Crichton RR. Iron, brain ageing and neurodegenerative disorders. Nat Rev Neurosci. 2004;5:863–873.
- Carri MT, Ferri A, Cozzolino M, Calabrese L, Rotilio G. Neurodegeneration in amyotrophic lateral sclerosis: the role of oxidative stress and altered homeostasis of metals. Brain Res Bull. 2003;61:365–374.
- Graeber MB, Raivich G, Kreutzberg GW. Increase of transferrin receptors and iron uptake in regenerating motor neurons. J Neurosci Res. 1989;23:342–345.
- Kasarskis EJ, Tandon L, Lovell MA, Ehmann WD. Aluminum, calcium, and iron in the spinal cord of patients with sporadic amyotrophic lateral sclerosis using laser microprobe mass spectroscopy: a preliminary study. J Neurol Sci. 1995;130:203–208.
- Olsen MK, Roberds SL, Ellerbrock BR, Fleck TJ, McKinley DK, et al. Disease mechanisms revealed by transcription profiling in SOD1-G93A transgenic mouse spinal cord. Ann Neurol. 2001;50:730–740.
- Jeong SY, Rathore KI, Schulz K, Ponka P, Arosio P, et al. Dysregulation of iron homeostasis in the CNS contributes to disease progression in a mouse model of amyotrophic lateral sclerosis. J Neurosci. 2009;29:610–619.
- Wang Q, Zhang X, Chen S, Zhang S, Youdium M, et al. Prevention of motor neuron degeneration by novel iron chelators in SOD1(G93A) transgenic mice of amyotrophic lateral sclerosis. Neurodegener Dis. 2011;8:310–321.
- Nandar W, Connor JR. HFE gene variants affect iron in the brain. J Nutr. 2011;141:729S–739S.
- Goodall EF, Greenway MJ, van Marion I, Carroll CB, Hardiman O, et al. Association of the H63D polymorphism in the hemochromatosis gene with sporadic ALS. Neurology. 2005;65:934–937.
- Restagno G, Lombardo F, Ghiglione P, Calvo A, Cocco E, et al. HFE H63D polymorphism is increased in patients with amyotrophic lateral sclerosis of Italian origin. J Neurol Neurosurg Psychiatry. 2007;78:327.
- Wang XS, Lee S, Simmons Z, Boyer P, Scott K, et al. Increased incidence of the Hfe mutation in amyotrophic lateral sclerosis and related cellular consequences. J Neurol Sci. 2004;227:27–33.
- Sutedja NA, Sinke RJ, Van Vught PW, Van der Linden MW, Wokke JH, et al. The association between H63D mutations in HFE and amyotrophic lateral sclerosis in a Dutch population. Arch Neurol. 2007;64:63–67.
- Schymick JC, Talbot K, Traynor BJ. Genetics of sporadic amyotrophic lateral sclerosis. Hum Mol Genet. 2007;16 Spec No. 2:R233–242.
- van Es MA, van Vught PW, Blauw HM, Franke L, Saris CG, et al. Genetic variation in DPP6 is associated with susceptibility to amyotrophic lateral sclerosis. Nat Genet. 2008;40:29–31.
- Anderson LJ, Holden S, Davis B, Prescott E, Charrier CC, et al. Cardiovascular T2-star (T2*) magnetic resonance for the early diagnosis of myocardial iron overload. Eur Heart J. 2001;22:2171–2179.
- Duyn JH. High-field MRI of brain iron. Methods Mol Biol. 2011;711:239–249.
- Stark DD. Hepatic iron overload: paramagnetic pathology. Radiology. 1991;179:333–335.
- Tsushima Y, Endo K. Hypointensities in the brain on T2*-weighted gradient-echo magnetic resonance imaging. Curr Probl Diagn Radiol. 2006;35:140–150.
- Duyn JH, van Gelderen P, Li TQ, de Zwart JA, Koretsky AP, et al. High-field MRI of brain cortical substructure based on signal phase. Proc Natl Acad Sci U S A. 2007;104:11796–11801.
- Brooks BR, Miller RG, Swash M, Munsat TL. El Escorial revisited: revised criteria for the diagnosis of amyotrophic lateral sclerosis. Amyotroph Lateral Scler Other Motor Neuron Disord. 2000;1:293–299.
- Litvan I, Mangone CA, Werden W, Bueri JA, Estol CJ, et al. Reliability of the NINDS Myotatic Reflex Scale. Neurology. 1996;47:969–972.
- Bohannon RW, Smith MB. Interrater reliability of a modified Ashworth scale of muscle spasticity. Phys Ther. 1987;67:206–207.
- Yousry TA, Schmid UD, Alkadhi H, Schmidt D, Peraud A, et al. Localization of the motor hand area to a knob on the precentral gyrus. A new landmark. Brain. 1997;120:141–157.
- Deng HX, Zhai H, Bigio EH, Yan J, Fecto F, et al. FUS-immunoreactive inclusions are a common feature in sporadic and non-SOD1 familial amyotrophic lateral sclerosis. Ann Neurol. 2010;67:739–748.
- Smith MA, Harris PL, Sayre LM, Perry G. Iron accumulation in Alzheimer disease is a source of redox-generated free radicals. Proceedings of the National Academy of Sciences of the United States of America. 1997;94:9866–9868.
- Jones EG, Coulter JD, Wise SP. Commissural columns in the sensory-motor cortex of monkeys. J Comp Neurol. 1979;188:113–135.
- Udaka F, Kameyama M, Tomonaga M. Degeneration of Betz cells in motor neuron disease. A Golgi study. Acta Neuropathol. 1986;70:289–295.
- Zhang L, Ulug AM, Zimmerman RD, Lin MT, Rubin M, et al. The diagnostic utility of FLAIR imaging in clinically verified amyotrophic lateral sclerosis. J Magn Reson Imaging. 2003;17:521–527.
- Rouault TA, Cooperman S. Brain iron metabolism. Semin Pediatr Neurol. 2006;13:142–148.
- Hallgren B, Sourander P. The effect of age on the non-haemin iron in the human brain. J Neurochem. 1958;3:41–51.
- Connor JR, Menzies SL, St Martin SM, Mufson EJ. Cellular distribution of transferrin, ferritin, and iron in normal and aged human brains. J Neurosci Res. 1990;27:595–611.
- Morris CM, Candy JM, Oakley AE, Bloxham CA, Edwardson JA. Histochemical distribution of non-haem iron in the human brain. Acta Anat (Basel) 1992;144:235–257.
- Bartzokis G, Cummings JL, Markham CH, Marmarelis PZ, Treciokas LJ, et al. MRI evaluation of brain iron in earlier- and later-onset Parkinson's disease and normal subjects. Magn Reson Imaging. 1999;17:213–222.
- Dexter DT, Wells FR, Agid F, Agid Y, Lees AJ, et al. Increased nigral iron content in postmortem parkinsonian brain. Lancet. 1987;2:1219–1220.
- Jellinger KA. The role of iron in neurodegeneration: prospects for pharmacotherapy of Parkinson's disease. Drugs Aging. 1999;14:115–140.
- Braak H, Ghebremedhin E, Rub U, Bratzke H, Del Tredici K. Stages in the development of Parkinson's disease-related pathology. Cell Tissue Res. 2004;318:121–134.
- Mizuno Y, Amari M, Takatama M, Aizawa H, Mihara B, et al. Transferrin localizes in Bunina bodies in amyotrophic lateral sclerosis. Acta Neuropathol. 2006;112:597–603.
- Goodall EF, Haque MS, Morrison KE. Increased serum ferritin levels in amyotrophic lateral sclerosis (ALS) patients. J Neurol. 2008;255:1652–1656.
- Mitchell RM, Simmons Z, Beard JL, Stephens HE, Connor JR. Plasma biomarkers associated with ALS and their relationship to iron homeostasis. Muscle Nerve. 2010;42:95–103.
- Mitchell RM, Freeman WM, Randazzo WT, Stephens HE, Beard JL, et al. A CSF biomarker panel for identification of patients with amyotrophic lateral sclerosis. Neurology 2008
- Konijn AM, Carmel N, Levy R, Hershko C. Ferritin synthesis in inflammation. II. Mechanism of increased ferritin synthesis. Br J Haematol. 1981;49:361–370.
- Jeong SY, Crooks DR, Wilson-Ollivierre H, Ghosh MC, Sougrat R, et al. Iron insufficiency compromises motor neurons and their mitochondrial function in Irp2-null mice. PLoS One. 2011;6:e25404.
- Henkel JS, Beers DR, Zhao W, Appel SH. Microglia in ALS: the good, the bad, and the resting. J Neuroimmune Pharmacol. 2009;4:389–398.
- Neumann H, Kotter MR, Franklin RJ. Debris clearance by microglia: an essential link between degeneration and regeneration. Brain. 2009;132:288–295.
- Ward RJ, Crichton RR, Taylor DL, Della Corte L, Srai SK, et al. Iron and the immune system. J Neural Transm. 2011;118:315–328.
- Simmons DA, Casale M, Alcon B, Pham N, Narayan N, et al. Ferritin accumulation in dystrophic microglia is an early event in the development of Huntington's disease. Glia. 2007;55:1074–1084.
- Pitt D, Boster A, Pei W, Wohleb E, Jasne A, et al. Imaging cortical lesions in multiple sclerosis with ultra-high-field magnetic resonance imaging. Arch Neurol. 2010;67:812–818.
- Connor JR, Boeshore KL, Benkovic SA, Menzies SL. Isoforms of ferritin have a specific cellular distribution in the brain. J Neurosci Res. 1994;37:461–465.
- Williams R, Buchheit CL, Berman NE, LeVine SM. Pathogenic implications of iron accumulation in multiple sclerosis. J Neurochem. 2012;120:7–25.
- Cass WA, Grondin R, Andersen AH, Zhang Z, Hardy PA, et al. Iron accumulation in the striatum predicts aging-related decline in motor function in rhesus monkeys. Neurobiol Aging. 2007;28:258–271.
- Duara R, Margolin RA, Robertson-Tchabo EA, London ED, Schwartz M, et al. Cerebral glucose utilization, as measured with positron emission tomography in 21 resting healthy men between the ages of 21 and 83 years. Brain. 1983;106(Pt 3):761–775.
- Wijesekera LC, Leigh PN. Amyotrophic lateral sclerosis. Orphanet J Rare Dis. 2009;4:3.
- Benarroch EE. Brain iron homeostasis and neurodegenerative disease. Neurology. 2009;72:1436–1440.
Source: PubMed