Evaluation of Multiple System Atrophy and Early Parkinson's Disease Using $^{123)I$-FP-CIT SPECT

$^{123)I$-FP-CIT SPECT를 이용한 다중계위축증 및 조기 파킨슨병에서의 평가

  • Oh, So-Won (Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital) ;
  • Kim, Yu-Kyeong (Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital) ;
  • Lee, Byung-Chul (Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital) ;
  • Kim, Bom-Sahn (Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital) ;
  • Kim, Ji-Sun (Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital) ;
  • Kim, Jong-Min (Department of Neurology, Seoul National University College of Medicine, Seoul National University Bundang Hospital) ;
  • Kim, Sang-Eun (Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital)
  • 오소원 (서울대학교 의과대학, 분당서울대학교병원 핵의학과) ;
  • 김유경 (서울대학교 의과대학, 분당서울대학교병원 핵의학과) ;
  • 이병철 (서울대학교 의과대학, 분당서울대학교병원 핵의학과) ;
  • 김범산 (서울대학교 의과대학, 분당서울대학교병원 핵의학과) ;
  • 김지선 (서울대학교 의과대학, 분당서울대학교병원 핵의학과) ;
  • 김종민 (서울대학교 의과대학, 분당서울대학교병원 신경과) ;
  • 김상은 (서울대학교 의과대학, 분당서울대학교병원 핵의학과)
  • Published : 2009.02.28

Abstract

Purpose: We investigated quantification of dopaminergic transporter (DAT) and serotonergic transporter (SERT) on $^{123}I$-FP-CIT SPECT for differentiating between multiple systemic atrophy (MSA) and idiopathic Parkinson's disease (IPD). Materials and Methods: N-fluoropropyl-$2{\beta}$-carbomethoxy-$3{\beta}$-4-[$^{123}I$]-iodophenylnortropane SPECT ($^{123}I$-FP-CIT SPECT) was performed in 8 patients with MSA (mean age: $64.0{\pm}4.5yrs$, m:f=6:2), 13 with early IPD (mean age: $65.5{\pm}5.3yrs$, m:f=9:4), and 12 healthy controls (mean age: $63.3{\pm}5.7yrs$, m:f=8:4). Standard regions of interests (ROls) of striatum to evaluate DAT, and hypothalamus and midbrain for SERT were drawn on standard template images and applied to each image taken 4 hours after radiotracer injection. Striatal specific binding for DAT and hypothalamic and midbrain specific binding for SERT were calculated using region/reference ratio based on the transient equilibrium method. Group differences were tested using ANOVA with the postHoc analysis. Results: DAT in the whole striatum and striatal subregions were significantly decreased in both patient groups with MSA and early IPD, compared with healthy control (p<0.05 in all). In early IPD, a significant increase in the uptake ratio in anterior and posterior putamen and a trend of increase in caudate to putamen ratio was observed. In MSA, the decrease of DAT was accompanied with no difference in the striatal uptake pattern compared with healthy controls. Regarding the brain regions where $^{123}I$-FP-CIT binding was predominant by SERT, MSA patients showed a decrease in the binding of $^{123}I$-FP-CIT in the pons compared with controls as well as early IPD patients (MSA: $0.22{\pm}0.1$ healthy controls: $0.33{\pm}0.19$, IPD: $0.29{\pm}0.19$), however, it did not reach the statistical significance. Conclusion: In this study, the differential patterns in the reduction of DAT in the striatum and the reduction of pontine $^{123}I$-FP-CIT binding predominant by SERT could be observed in MSA patients on $^{123}I$-FP-CIT SPECT. We suggest that the quantification of SERT as well as DAT using $^{123}I$-FP-CIT SPECT is helpful to differentiate parkinsonian disorders in early stage.

목적: 본 연구는 다중계위축증(MSA)과 원발성 파킨슨병(IPD)의 감별 진단을 위하여 $^{123}I$-FP-CIT SPECT를 사용하여 선조체내 도파민신경시스템 및 선조체외의 모노아민시스템을 평가하였다. 대상 및 방법: 총 13명의 IPD 환자(남:여=9:4, $65.5{\pm}5.3$세), 8명의 MSA 환자(남:여=6:2, $64.0{\pm}4.5$세), 정상인 12명(남:여=8:4, $63.3{\pm}5.7$세)에게 $^{123}I$-FP-CIT SPECT를 시행하였다. 도파민 운반체 분석을 위해 선조체내 미상핵과 전, 후피각에 관심영역을 설정하고 세로토닌 운반체 분석을 위해 시상하부와 뇌교에 관심영역을 각각 정한 뒤 각 부위에서 $^{123}I$-FP-CIT의 결합잠재능(binding potential, BP=V3")을 계산하였다. V3"는 비특이적 결합에 대한 특이 결합의 비율을 이용하여 구하였고 비특이적 결합 부위는 후두엽 영역에서 계수를 측정하였다. 결과: 선조체 전체 및 미상핵과 전후피각 각각에서의 도파민 운반체의 농도는 MSA와 IPD환자 모두에서 정상인에 비해 현저한 감소를 나타내었다(p<0.05). 특히 IPD환자 군에서는 후측 피각에서의 도파민 운반체 농도에 심한 감소를 보여 전후피각비가 정상군에 비하여 유의하게 증가되었으며($1.55{\pm}0.34$ vs. $1.29{\pm}0.06$, p=0.026), 미상핵/피각비은 증가된 양상을 보였으나 유의수준에 도달하지는 못하였다($1.24{\pm}0.20$ vs. $1.11{\pm}0.06$, p=0.23). MSA의 경우 전후피각비($1.32{\pm}0.19$)와 미상핵/피각비($1.07{\pm}0.25$)에서 정상군과 차이가 없었다. 세로토닌 운반체에 의한 뇌교에서의 섭취는 MSA환자군에서 정상군 및 IPD환자군에 비하여 감소되어 있는 경향을 나타내었으며(정상:$0.33{\pm}0.19$, IPD: $0.29{\pm}0.19$, MSA: $0.22{\pm}0.1$) 시상하부에서는 각 군에서 뚜렷한 차이가 없었다. 결론: 본 연구에서 $^{123}I$-FP-CIT SPECT 영상을 이용하여 IPD와 MSA환자의 선조체 도파민 운반체의 감소정도와 양상을 평가하고, 뇌교 및 시상하부에서의 세로토닌 운반체 섭취의 감소를 평가하였다. $^{123}I$-FP-CIT SPECT에 의한 선조체내 도파민 운반체 변화 및 뇌교에서의 세로토닌 운반체의 변화의 가시화 및 정량화는 MSA와 IPD의 조기 감별에 도움이 유용할 것이다.

Keywords

References

  1. Bannister R, Oppenheimer DR. Degenerative diseases of the nervons system associated with autonomic failure. Brain 1972;95:457-74 https://doi.org/10.1093/brain/95.3.457
  2. Spokes EG, Bannister R, Oppenheimer DR. Multiple system atrophy with autonomic failure: Clinical, histological and neurochemical observations in four cases. J Neurol Sci 1979;43:59-82 https://doi.org/10.1016/0022-510X(79)90073-X
  3. Feamley JM, Lees A. Striatonigral degeneration. A clinicopathological study. Brain 1990;113:1823-43 https://doi.org/10.1093/brain/113.6.1823
  4. Wenning GK, Ben Shlomo Y, Magalhaes M, Daniel SE, Quinn NP. The clinical features and natural history of multiple system atrophy: an analysis of 100 cases. Brain 1994;117:835-45 https://doi.org/10.1093/brain/117.4.835
  5. Quinn N. Multiple system atrophy: the nature of the beast. J Neurol Neurosurg Psychiatry 1989;32:1358-63 https://doi.org/10.1136/jnnp.52.Suppl.78
  6. Litvan I, Goetz CG, Jankovic J, Wenning GK, Booth V, Bartko JJ, et al. What is the accuracy of the clinical diagnosis of multiple system atrophy? A clinicopathologic study. Acta Neurol 1997;54:937-44 https://doi.org/10.1001/archneur.1997.00550200007003
  7. Wenning GK, Tison F, Ben Shlomo Y, Daniel SE, Quim NP. Multiple system atrophy: a review of 203 pathologically proven cases. Mov Disord 1997;12:133-47 https://doi.org/10.1002/mds.870120203
  8. Kaufman MJ, Madras BK Severe depletion of cocaine recognition sites associated with the dopamin transporter in Parkinson's disease striatum. Synapse 1991;9:43-9 https://doi.org/10.1002/syn.890090107
  9. Niznik HB, Fogel EF, Fassos FF, Seeman P. The dopamine transporter is absent in parkinsonism putamen and rednced in caudate nuclens. J Neurochem 1991;56:192-8 https://doi.org/10.1111/j.1471-4159.1991.tb02580.x
  10. Br${\ddot{u}}cke T, Djamshidian S, Bencsits G, Pirker W, Asenbaum S, Podreka I. SPECT and PET imaging of the dopaminergic system in Parkinson's disease. J Neurol 2000;247(suppl 4):2-7 https://doi.org/10.1007/PL00007769
  11. Kim YJ, Ichise M, Ballinger JR, Vines D, Erami SS, Tatschida T, et al. Combination of dopamine transporter and $D_2$ receptor SPECT in the diagnostic evaluation of PD, MSA, and PSP. Mov Disord 2002; 17:303-12 https://doi.org/10.1002/mds.10042
  12. Pirker W, Asenbaum S, Bencsits G, Prayer D, Gerschlager W, Deecke L, et al. [$^{123}I$]beta-CIT SPECT in multiple system atrophy, progressive supranuclear palsy, and cortocobasal degeneration. Mov Disord 2000;15:1158-67 https://doi.org/10.1002/1531-8257(200011)15:6<1158::AID-MDS1015>3.0.CO;2-0
  13. Varrone A, Marek KL, Jennings D, Innis RB, Seibyl JP. [$^{123}I$] beta-CIT SPECT imaging demonstrates reduced density of striatal dopamine transporters in Parkinson's disease and multiple system atrophy. Mov Disord 2001;16:1023-32 https://doi.org/10.1002/mds.1256
  14. Benarroche EE, Schmeichel AM, Low PA, Parisi JE. Involvement of medullary serotonergic groups in multiple system atrophy. Ann Neurol 2004;55:418-22 https://doi.org/10.1002/ana.20021
  15. Patel T, Marek K, Innis RB, Seibyl JP. No difference in 5-HT transporter density in idiopathic Parkinson's disease subjects and healthy controls using $^{123}I-{\Beta}-CIT$ SPECT. J Nucl Med 2000; 41(suppl):221
  16. Kim SE, Choi JY, Choe YS, Choi Y, Lee WY. Serotonin transporters in the midbrain of Parkinson's disease patients : a study with $^{123}I-{\Beta}-CIT$ SPECT. J Nucl Med 2003;44:870-6
  17. Neumeyer JL, Wang SY, Milins RA, Baldwin RM, Zea-Ponce Y, Hoffer PB, et al. $^{123}I-2{\Beta}-$-carbomethoxy-$3{\Beta}$-(4-iodo-phenyl)tropane (${\Beta}-CIT$). High affinity SPECT radiotracer of monoamine reuptake sites in brain. J Med Chem 1991;34:3144-6 https://doi.org/10.1021/jm00114a027
  18. Boja JW, Mitchell WM, Patel A, Kopajtic TA, Carroll FI, Lewin AH, et al. High-affinity binding of [$^{125}I$]RTI-55 to dopamine and serotonin transporters in rat brain. Synapse 1992;12:27-36 https://doi.org/10.1002/syn.890120104
  19. Booij J, Andringa G, Rijks LJ, Vermeulen RJ, De Bruin K, Boer GJ, et al. [$^{125}I$] FP-CIT binds to the dopamine transporter as assessed by biodistribution studies in rats and SPECT studies in MPTP lesioned monkeys. Synapse 1997;27:183-90 https://doi.org/10.1002/(SICI)1098-2396(199711)27:3<183::AID-SYN4>3.0.CO;2-9
  20. Booij J, Tissingh G, Boer GJ, Speehuan JD, Stoof JC, Janssen AG, et al. [$^{125}I$] FP-CIT SPECT shows a pronounced decline of striatal dopamine transporter labelling in early and advanced Parkinson's disease. J Neurol Neurosurg Psychiatry 1997;62:133-40 https://doi.org/10.1136/jnnp.62.2.133
  21. Booij J, Habraken JB, Bergmans P, Tissingh G, Winogrodzka A, Wolters EC, et al. Imaging of dopamine transporters with iodine-123-FP CIT SPECT in healthy controls and patients with Parkinson's disease. J Nucl Med 1998;39:1879-84
  22. Booij J, Habraken JB, Bergmans P, Tissingh G, Winogrodzka A, Wolters EC, et al. Iodine-123 N-omega-fluoropropyl-2${\Beta}$- carbomethoxy-3${\Beta}$-(4-iodophenyl)tropane SPEeT in healthy controls and early-stage, drug-naive Parkinson's disease. J Nucl Med 1998;39:1143-8
  23. Hughes AJ, Daniel SE, Kilford L, Lees AJ. Accuracy of clinical diagnosis of idiopathic Parkinson's disease: a clinico-pathological study of 100 cases. J Neurol Neurosurg Psychiatry 1992;55:181-4 https://doi.org/10.1136/jnnp.55.3.181
  24. Gilman S, Low PA, Quinn N, Albanese A, Ben-Shlomo Y, Fowler CJ, et al. Consensus statement on the diagnosis of multiple system atrophy. J Neurol Sci 1999;163:94-8 https://doi.org/10.1016/S0022-510X(98)00304-9
  25. Okada T, Fujita M, Shimada S, Sato K, Schloss P, Watanabe Y, et al. Assessment of affinities of beta-CIT, beta-CIT-FE, and beta-CIT-FP for monoamine transporter permanently expressed in cell lines. Nul Med & Biol 1998;35:53-8
  26. Neumeyer JL, Tamagnan G, Wang S, Gao Y, Miliius RA, Kula NS, et al. N-substituted analogs of 2 beta-carbomethoxy-3 beta-(4'-iodophenyl)tropane (beta-CIT) with selective affinity to dopamine or serotonin transporters in rat forebrain. J Med Chem 1996;39:543-8 https://doi.org/10.1021/jm9505324
  27. G${\ddot{u}}$nther I, Hall H, Halldin C, Swahn CG, Farde L, Sedvall G. $[^{125}I$] ${\Beta}$-CIT-FD and G. $[^{125}I$] ${\Beta}$-CIT-FP are superior to G. $[^{125}I$] ${\Beta}$-CIT for dopamine transporter visualization : Autoradiographic evaluation in the human brain. Nul Med & Bioi 1997;24:629-34 https://doi.org/10.1016/S0969-8051(97)00081-4
  28. Berding G, Br${\ddot{u}}$cke T, Odin P, Brooks DJ, Kolbe H, Gielow P, et al. $[^{125}I$] beta-CIT SPECT imaging of dopamine and serotonin transporters in Parkinson's disease and multiple system atrophy. Nuklearmedizin 2003;42:31-8
  29. Malison RT, Price LH, Berman R, van Dyck CH, Pelton GH, Carpenter L, et al. Reduced brain serotonin transporter availability in major depression as measured by $[^{125}I$]-2 beta-carbomethoxy-3 beta-(4-iodophenyl)tropane and single photon emission computed tomogrphy. Biol Psychiatry 1998;44:1090-8 https://doi.org/10.1016/S0006-3223(98)00272-8
  30. Willeit M, Praschak-Rieder N, Neumeister A, Pirker W, Asenbaum S, Vitouch O, et al. $[^{125}I$]-beta-CIT SPECT imaging shows reduced brain serotonin transporter availability in drug-free depressed patients with seasonal affective disorder. Biol Psychiat 2000;47:482-9 https://doi.org/10.1016/S0006-3223(99)00293-0
  31. Tohgi H, Abe T, Takahashi S, Tahahashi J, Hamato H. Concentrations of serotonin and its related substances in the cerebrospinal fluid of Parkinsonian patients and their relations to the severity of symptoms. Neurosci Lett, 1993; 150: 71-4 https://doi.org/10.1016/0304-3940(93)90111-W
  32. Chinaglia G, Landwehrmeyer B, Probst A, Palacios JM. Serotonergic terminal transporters are differentially affected in Parkinson's disease and progressive supranuclear palsy: an autoradiographic study with [$^{3}H$]citalopram. Neuroscience 1993;54:691-9 https://doi.org/10.1016/0306-4522(93)90240-G
  33. Halliday GM, Blumbergs PC, Cotton RGH, Blessing WW, Geffer LB. Loss of brainstem serotonin- and substance P-containing neurons in Parkinson's disease. Brain Res 1990;510:104-7 https://doi.org/10.1016/0006-8993(90)90733-R
  34. Miyawaki E, Meah Y, Koller We. Serotonin, dopamine, and motor effects in Parkinson's disease. Clin Neuropharmacol 1997;20:300-310 https://doi.org/10.1097/00002826-199708000-00002
  35. Haapaniemi TH, Ahonen A, Torniainen P, Sotaniemi KA, Myllyla VV. [$^{123}I$]beta-CIT SPECT demonstrates decreased brain dopamine and serotonin transporter levels in untreated parkinsonian patients. Mov Disord 2001;167:124-30