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1 대한임상신경생리학회지 16(1):1-7, 2014 eissn pissn Review 신경계질환에서철관련자기공명영상기법의활용 양산부산대학교병원신경과, 의생명연구소 Application of Iron Related Magnetic Resonance Imaging in the Neurological Disorders Tae-Hyoung Kim, Jae-Hyeok Lee Department of Neurology, Pusan National University Yangsan Hospital, Research Institute for Convergence of Biomedical Science and Technology, Yangsan, Korea Iron is an important element for brain oxygen transport, myelination, DNA synthesis and neurotransmission. However, excessive iron can generate reactive oxygen species and contribute neurotoxicity. Although brain iron deposition is the natural process with normal aging, excessive iron accumulation is also observed in various neurological disorders such as neurodegeneration with brain iron accumulation, Parkinson s disease, Alzheimer s disease, multiple sclerosis, Friedreich ataxia, and others. Magnetic resonance image (MRI) is a useful method for detecting iron deposits in the brain. It can be a powerful tool for diagnosis and monitoring, while furthering our understanding of the role of iron in the pathophysiology of a disease. In this review, we will introduce the mechanism of iron toxicity and the basics of several iron-related MRI techniques. Also, we will summarize the previous results concerning the clinical application of such MR imagings in various neurological disorders. (Korean J Clin Neurophysiol 2014;16:1-7) Key Words: Iron, Neurodegenerative disorders, MRI Received 5 June 2014; accepted 13 June 서 론 철은 DNA 합성, 유전자발현, 수초화, 신경물질전달 (neurotransmission), 미토콘드리아의전자수송등에관여한다. 1 뇌내에서철은헤모글로빈에있는헴철 (heme iron) 과페 Address for correspondence; Jae-Hyeok Lee Department of Neurology, Pusan National University Yangsan Hospital, Beomo-ri, Mulgum-eup, Yangsan , Korea Tel: Fax: jhlee.neuro@pusan.ac.kr * This study was supported by a grant from the Pusan National University Yangsan Hospital (2014). 리틴 (ferritin), 트랜스페린 (transferin), 헤모시데린 (hemosiderin) 등의비헴철 (non-heme iron) 로구분된다. 트랜스페린은혈액내철을뇌조직으로수송하고, 페리틴은철을저장하여안정된상태로유지한다. 1,2 페리틴의분해산물인헤모시데린은출혈이나철이과도하게축적되는경우에관찰된다. 1 철 (free iron), 페리틴, 트랜스페린은주로희소돌기아교세포, 성상세포, 소교세포등에분포하며, 이중희소돌기아교세포는뇌내철의가장주된저장소다. 2,3 뇌내철의침착은주로창백핵 (globus pallidus), 흑색질 (substantia nigra), 적색핵 (red nucleus), 치아핵 (dentate nucleus), 꼬리핵 (caudate nucleus), 조가비핵 (putamen), 대뇌피질 (cerebral cortex) 등의특정뇌영역에서잘관찰되며, 뇌내철의양은정상발달과노화과정에서점차증가한다. 4 Copyright 2014 by The Korean Society of Clinical Neurophysiology 1

2 과도하게축적된철은활성산소 (reactive oxygen species, ROS) 를생성하여산화스트레스 (oxidative stress) 를유발하고, 신경퇴행성질환들의주요발병원인으로여겨지며 1,2,5, 이와연관된질환들로는 neurodegeneration with brain iron accumulation (NBIA) 질환들, 파킨슨병 (Parkinson s disease) 과비전형파킨슨증후군 (atypical parkinsonism), 알츠하이머병 (Alzheimer s disease), 다발성경화증 (multiple sclerosis) 등이있다. 1,3,5,6 자기공명영상 (MRI, Magnetic resonance imaging) 은생체내철침착정도를간접적으로측정할수있는유용한검사법으로고자기장스캐너와영상기법의발달은뇌내철의침착과관련된각종신경퇴행성질환의진단및연구에많은도움을주고있다. 6 최근에는초고자기강도 7T MRI 가도입되어병변을병리조직소견과비슷한해상도로확인할수있게되었다. 7 본문에서는과도한철에의한신경독성기전, 뇌내철을영상화하는자기공명영상기법, 그리고앞서언급한다양한신경퇴행성질환들의철과관련된병태생리와영상학적소견에대해언급하고자한다. 철독성의기전정상상태에서세포내의철은대부분페리틴에결합한안정된상태로저장되지만, 페리틴이결핍되거나파괴되는경우, 유리철 (free iron) 의양이증가하게된다. 4 산화환원반응성 (redox-active) 을가지는유리철은펜톤반응 (Fenton reaction) 을통해활성산소종을생성한다. 1,2,4-6 펜톤반응은다음과같다. (1) Fe 2+ + H 2O 2 Fe 3+ + HO + OH (2) Fe 3+ + H 2O 2 Fe 2+ + HOO + H + (1) 2가철 (Fe 2+ ) 은과산화수소 (H 2O 2) 와반응하여 3가철 (Fe 3+ ) 과수산기라디칼 (hydroxyl radical, HO ), 수산화물이온 (hydroxide ion, OH ) 을생성하고, (2) 3가철은과산화수소와반응하여 2가철과과산화물라디칼 (superoxide radical, HOO ), 양성자 (proton, H + ) 을생성한다. 활성산소종은세포막의인지질에있는다불포화지방산의과산화를유발하여활성알데히드의생성을촉진한다. 이들은독성이매우강해단백질의번역후변형 (post-translational modification) 과활성단백질산화물을형성하여단백질의손상을일으킨다. 1 손상되고잘못접힌 (misfolded) 단백질들은서로잘응집되며, 유비퀴틴프로테아좀 (ubiquitin/proteasome) 단백질가 수분해시스템의처리능력보다많이생성될경우세포내봉입체의형태로축적된다. 1,8 자기공명영상을통한뇌내철침착의영상화자기공명영상은비헴철의함량을정량적으로측정할수있다. 철함량이높은뇌영역에서페리틴이비헴철의 80% 이상을차지하기때문에자기공명영상에영향을미치는주된인자는페리틴이다. 6,9,10 철함량을정량적으로측정할수있는자기공명영상기법들은다음과같다. Relaxation metrics 다양한자기공명영상기법들중에서종축이완시간 (T2, T2', T2 * ) 과종축이완속도 (R2=1/T2, R2'=1/T', R2 * =1/T2 * ) 를이용한이완기법 (relaxation metrics) 이가장널리사용되었다. 6,11,12 자기공명영상에서 T2, T2', T2 * 는다음과같이설명할수있다. 6, 고주파펄스 (radiofrequency pulse) 를주면모든양성자스핀들은횡축자화벡터로변하면서 x-y 평면으로이동하여동위상상태가된다. 펄스를중단하면시간이지나면서자기장의불균일성과양성자들의스핀-스핀상호작용에의해횡축자화벡터가 x-y 평면상에서서서히흩어지는탈위상 (dephasing) 이시작된다. 이러한횡축자화벡터의붕괴는시간상수 T2로주어지는특징화된비율로진행되며, 이를 T2 이완 (T2 transverse relaxation time, spin-spin relaxation time) 이라고한다. 조직의 T2 이완은양성자마다느끼는자기장의세기가달라져서생기는스핀- 스핀상호작용에의존하여발생하는현상이며, 모든조직의고정된값이다. T2 * 는스핀-스핀상호작용뿐만아니라, 외부자기장의불균일성에의해발생하는탈위상화를같이반영한다. T2 * 는외부자기장의불균일성 (ΔB) 에의존해그값이고정되어있지않으며, T2와의관계는 {1/T2 * = 1/T2 + γ ΔB, γ ΔB=1/T2', γ=gyromagnetic ratio} 로표현된다. T1은종축인 z축을따라재정렬하는시간으로종축이완시간 (longitudinal relaxation time, spinlattice relaxation time) 이라고한다. 자기공명영상에서영상대조는특정영역간의물농도의차이및양성자의 T1, T2의차이에의해결정되며, 상자성 (paramagnetic) 을띄는철은 T2 이완시간을감소시켜 T2 강조영상에서저신호강도로, R2 영상에서는고신호강도로나타난다. T2 * 강조영상은상자성인철에의한외부자기장의불균일성의영향을받아 T2보다더욱더강조된저신호강도로나타나게된다. R2 는 R2 * 와 R2사이의차이값으로 (R2 =R2 * -R2), 스핀-스핀상호작용의영향을제외한외부자기장의불균일 2 Korean J Clin Neurophysiol / Volume 16 / June 2014

Iron Related MRI 성을잘반영한다. 기존의연구들은 R2, R2, R* 값이사후뇌조직에서측정한철의농도와높은상관관계를가지고있다고보고하였다. 11-13 한연구에서 R2* 가 R2보다더우수한상관성을나타냈다. 13 하지만염증, 신경아교증, 부종, Waller 변성과같이조직내물성분이증가하면이러한영상들의신호강도에영향을준다.

0T) 로얻어진 R2 영상간의차이를구해서얻어진다. 15 이는자기장의세기가커짐에따라페리틴의농도에비례해서 R2값이변화하는성질을이용한것이다. Bartzokis 등은사후뇌조직내철의함량과높은상관관계를보임을증명하였다. 16 하지만자기공명영상촬영을각각다른자기장의세기로두번을찍어야하는단점이있다.

3 Iron Related MRI 성을잘반영한다. 기존의연구들은 R2, R2, R* 값이사후뇌조직에서측정한철의농도와높은상관관계를가지고있다고보고하였다 한연구에서 R2* 가 R2보다더우수한상관성을나타냈다. 13 하지만염증, 신경아교증, 부종, Waller 변성과같이조직내물성분이증가하면이러한영상들의신호강도에영향을준다. 6,10,14 R 는페리틴에특이도가높고, R2에영향을미치는여러인자들의영향을덜받는다는장점이있다. 6,14 Field dependent relaxivity increase FDRI (field dependent relaxivity increase) 는자기장의세기가다른두개의자기공명영상 ( 예를들면 0.5T와 1.5T, 또는 1.5T와 3.0T) 로얻어진 R2 영상간의차이를구해서얻어진다. 15 이는자기장의세기가커짐에따라페리틴의농도에비례해서 R2값이변화하는성질을이용한것이다. Bartzokis 등은사후뇌조직내철의함량과높은상관관계를보임을증명하였다. 16 하지만자기공명영상촬영을각각다른자기장의세기로두번을찍어야하는단점이있다. Susceptibility-weighted imaging 자기화율강조영상 (susceptibility-weighted imaging, SWI) 은고해상도의 3D 유동보상경사에코연쇄 (3D flow-compensated gradient echo sequence) 를이용하는영상기법이다. 14,17 자기신호강도만을이용하는기존의다른영상기법들과달리, SWI는철과같은상자성체로인해발생하는자기신호강도 (magnitude) 와자기화율의변화로인한위상값 (phase) 을둘다사용하는것이특징이다 (Fig. 1). 14,17 SWI는쉽게영상을얻을수있고, 공간해상도 (spatial resolution) 가높은것이장점이며, 특히미세출혈을관찰하는데유용하다. 17,18 위상차값 (phase shift value) 이사후뇌조직에서측정한철의농도와높은상관관계를보였으 나, 19 R2에비해헴철에의한영향을많이받는다는단점이있다. 실제로 SWI에서는다른영상에비해백질과회질간의신호강도차이가더욱뚜렷한데, 이는회질에서관찰되는저신호강도가비헴철뿐만아니라혈류에포함된헴철까지반영하기때문이다. 19,20 또한 SWI는구조물간의이질성에의한영상의뒤틀림과왜곡이심한데, 주로공기, 뼈, 조직등이서로접하는지점에서잘나타난다. 20 각질환별자기공명영상소견기존의연구들은자기공명영상을이용하여각질환에특징적인뇌내철침착의양상을보고하였다 (Table 1). 여기에서는철과관련된이들질환의병태생리적특징과자기공명영상소견을간략히기술하고자한다. Neurodegeneration with brain iron accumulation 뇌의특정영역에과도한철침착을보이는질환들을총칭하여 NBIA라고한다. 2,6,21 뇌자기공명영상에서 T2 혹은 T2* 저신호강도로관찰되며, 22,23 이는중요한진단적소견이다. 자기공명영상에서관찰되는철침착의분포양상은원인질환에따라각기다른특징을보여, 확진에필요한유전자검사를선택하는데도움을준다. 23 Pantothenate kinase-2-associated neurodegeneration (PKAN) 은가장흔한 NBIA 질환으로, pantothenate kinase 를코드화하는 PANK2 유전자의돌연변이로인해발병하는상염색체열성유전질환이다. 21,24 T2 강조영상에서창백핵가운데고신호강도부위가주변의저신호강도로둘러싸여있는 eye of the tiger 소견이특징적이다. 22,23 가운데 T2 고신호강도부위는신경아교증과부종을, 주변의저신호강도부위는철의과다침착을반영한다. 이러한소견이 PKAN만의특징적소견으로여겨졌으나, hereditary ferritinopathy와 A B C D Figure 1. Axial T2-wighted image (A) corresponding magnitude (B), phase (C), and susceptibility-weighted image after postprocessing (D). The phase image here is for left hand system. Korean J Clin Neurophysiol / Volume 16 / June

4 Table 1. Iron related magnetic resonance imaging in the various neurological disorders Disease Field strength Techniques Results References NBIA T2*, T2 FSE T2* and T2 FSE hypointensity showed disease-specific iron deposition and its distribution in NBIAs T T1, T2, SWI All patients with PKAN showed hyperintensity of the bilateral GP on T2WI and SWI. SWI demonstrated iron deposition in the GP better than conventional imaging. Parkinsonism 1.5T, 0.5T FDRI Earlier-onset PD patients had increased FDRI in SN, PUT and GP. 30 3T R2, R2*, R2 Mean SN values for R2 was lower, and R2* and R2 were higher in PD patients than in controls. R2* and R2 values were correlated with motor performance. 1.5T PRIME sequence (R2, R2*, R2 ) Mean SN values for R2* and R2 were higher in PD patients than in controls. R2 was lower in the PUT, and was correlated with disease duration. 3T SWI Iron concentration of SN was significantly increased in PD patients, and was correlated with UPDRS scores. 3T SWI SN iron concentration was increased in PD, and was correlated with Hoehn-Yahr scale, UPDRS scores, and serum ceruloplasmin levels. 3T SWI Significanlty increased phase shift values (left hand system) of PUT in MSA, and GP and TH in PSP, and subregional differences of hypointensity in the PUT, GP and TH between MSA-p and PSP were observed. 3T R2* PSP patients had higher R2* values in GP and CN, whereas MSA-p patients had higher R2* values in PUT than PD and controls. Increased R2* values were correlated with extent of atrophy which were observed in the most affected areas of each disorders. AD 1.5T, 0.5T FDRI Increased FDRI in CN and PUT were observed in AD patients T SWI The iron concentrations in the bilateral HP, PC, PUT, CN, and DN subregions of patients with AD were significantly higher than the controls, Moreover, especially those in the PC at the early stages of AD, were positively correlated with the severity of patients' cognitive impairment. 1.5T R2 Increased R2 values in temporal lobe gray matter, especially in hippocampus, and significant correlation between R2 values and reference postmortem iron concentration in healthy controls were observed. MS 1.5T T2 T2 hypointensity in gray matter areas correlated with progression of brain atrophy. 49 3T R2* R2* was inversely correlated with disease duration and higher total lesion load. 50 FA 1.5T R2* Higher R2* values in FA patients than in controls were observed. Treatment with deferiprone reduced R2* values significantly. ALS 1.5 T2* Hypointensities were found only in the precentral gyruses gray matter, and correlated with ALS. Functional Rating Scale. NBIA; Neurodegeneration with brain iron accumulation, PD; Parkinson s disease, AD; Alzheimer s disease, MS; multiple sclerosis, FA; Friedreich ataxia, ALS; amyotrophic lateral sclerosis, MSA; multiple system atrophy, PKAN; pantothenate kinase-2 associated neurodegeneration, PSP; progressive supranuclear palsy, FSE; fast spin echo, SWI; susceptibility weighted image, FDRI; field dependent relaxivity increase, PRIME; partially refocused interleaved multiple echo, GP; globus pallidus, SN; substantia nigra, PUT; putamen, TH; thalamus, HP; hippocampus, PC; parietal cortex, CN; caudate nucleus, DN; dentate nucleus Korean J Clin Neurophysiol / Volume 16 / June 2014

5 Iron Related MRI 다계통위축증과같은질환에서도관찰되었다. 25 유전검사로확진된 PKAN 환자의 SWI에서철과연관된저음영이흑색질에서창백핵을따라뚜렷하게분포하였다. 26 Neuroferritinopathy는페리틴의 L-chain을코드화하는 FTL 유전자의돌연변이로발병하는매우드문상염색체우성유전질환이다. 21,24 페리틴의구조적인결함으로정상적인철저장능이감소하고, 산화스트레스를일으키는유리철농도가증가한다. 27 자기공명영상에서과도한철의침착이치아핵, 창백핵, 흑색질, 꼬리핵, 조가비핵, 시상, 그리고대뇌피질등에서관찰되며, 22,23 질병의후기에는창백핵과조가비핵에서융합성고신호강도병변이보이기도한다. 23 Aceruloplasminemia는 ceruloplasmin을코드화하는 CP 유전자의돌연변이로생기는상염색체열성유전질환이다. 21,24 망막, 간, 췌장, 심장근육, 뇌에서철이침착되고, 뇌자기공명영상에서는선조체, 창백핵, 흑색질, 시상, 치아핵, 대뇌피질등에서철이축적된소견을보인다. 21,22,24 파킨슨병및비정형파킨슨증후군흑색질의과도한철축적은파킨슨병의특징적인병리소견중하나로, 8 사후병리조직학적연구들에서흑색질의철함량이정상에비해약 25% 에서 100% 가량증가된것을확인하였다. 28 정상인들은흑색질치밀부에비해흑색질그물부 (substantia nigra pars reticulate) 의철함량이더많으나파킨슨병환자들에서는흑색질치밀부 (substantia nigra pars compacta) 에서철침착이발생한다. 29 다양한자기공명영상기법들 (T2, R2*, FDRI, SWI 등 ) 로측정한흑색질의철함량이파킨슨병에서정상군에비해유의하게높았고, 운동증상의심한정도와양의상관관계를보였다 파킨슨병과비전형파킨슨증후군인진행핵상마비 (Progressive supranuclear palsy) 및파킨슨형다계통위축증 (Parkinsonian variant multiple system atrophy) 과의감별진단에자기공명영상을이용한뇌내철분석이유용하였다. 35,36 파킨슨병에비해비전형파킨슨증후군에서기저핵내철함량이더높았고, 보다광범위하게분포하였다. 35 또한각질환의주요병소에서병적인철침착이특히더심한경향을보였다. 36 병적철침착이파킨슨병의발병원인인지, 아니면신경퇴행성변화의부수현상인지에대해서는명확하게밝혀지지않았다. 초기파킨슨병이나파킨슨병의전구단계로알려진특발성렘수면장애에서정상인에비해철함량이증가하지않았다는연구결과는후자의가능성을보다더시사한다. 37,38 알츠하이머병알츠하이머병의사후병리조직에서신경세포, 신경원섬유매듭및플라크 (plaque) 내철의침착이관찰되었고, 39 과도한철이아밀로이드에의한신경독성과, 40 베타아밀로이드단백의응집을증가시킨다는연구결과가보고되었다. 41 Bartzokis 등은 FDRI 기법을이용하여알츠하이머병환자에서정상대조군에비해해마와꼬리핵및조가비핵의철농도가증가되었음을보여주었다. 42,43 과도한철의침착은젊은나이에발병한알츠하이머병환자들에서고령의환자들에비해더많이관찰되었다. 42 최근에는해마의페리틴철축적이조직손상과함께발생한다고보고하였다. 44 기억력저하를호소하는노인들을대상으로뇌의각영역의철농도를분석한결과, 정상대조군에비해측두엽의회백질, 특히해마 (hippocampus) 에서철의침착이증가되었다. 45,46 기타질환들다발성경화증환자의사후뇌조직을분석한결과, 조가비핵과시상의철함량이증가되어있었다. 47 자기공명영상을이용한생체내연구들에서정상군에비해기저핵, 시상, 그리고피질등의영역에서과도한철의축적이관찰되었으며, 48 회질내철침착은임상증상은물론병의중증도를반영하는뇌위축과유의한상관관계를보였다. 49,50 Friedrich ataxia (FA) 는미토콘드리아단백인 frataxin를코드화하는 FXN 유전자의돌연변이로발병하는상염색체열성유전질환이다. 2,24 Waldvogel 등은 R2* 영상을이용하여소뇌치아핵에철이과도하게축적되었음을관찰하였다. 51 FA 환자 9명에게철킬레이터 (chelator) 인 deferiprone 을 6개월간투여한결과임상증상의호전과더불어치아핵의 R2* 신호강도도유의하게감소하였다. 52 근위축성측색경화증 (Amyotrophic Lateral Sclerosis, ALS) 의환자들은철과연관된저음영이중심앞이랑 (precentral gyrus) 의회질에국한되어관찰되었다. 53 결론산화스트레스를유발하는과도한철축척은신경퇴행성질환들의주요발병원인이다. 자기공명영상은생체내철함량을간접적으로측정할수있어이들질환의진단과병리연구에유용하며, 최근에는영상대조도나해상도가개선된초고자기강도 (7.0 Tesla 이상 ) MRI가연구에활용되고있다. 앞으로뇌내철을측정하는데있어민감도, 특이도, 그리고해상도가향상된새로운자기공명영상기법들 Korean J Clin Neurophysiol / Volume 16 / June

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Lumbar spine

Lumbar spine CT 32 111 DOI : 10.3831/KPI.2010.13.2.111 Lumbar Spine CT 32 Received : 10. 05. 23 Revised : 10. 06. 04 Accepted : 10. 06. 11 Key Words: Disc herniation, CT scan, Clinical analysis The Clinical