[¹²³I]β-CIT SPECT imaging of dopamine and serotonin transporters in Parkinson’s disease and multiple system atrophy^[*]

Summary

Aims: Definition of the regional pattern of dopamine transporter (DAT) dysfunction in advanced Parkinson’s disease (PD) and evaluation of a potential correlation between DAT binding and symptoms; elucidation of the role of DAT imaging in the differential diagnosis of PD and multiple system atrophy (MSA); assessment and comparison of serotonin transporter (SERT) binding in PD and MSA. Methods: [¹²³I]ß-CIT SPECT was performed in 14 patients with advanced PD, 10 with moderate MSA and 20 healthy persons. Specific to nonspecific tracer binding ratios (V₃’’) were calculated via ROI analysis of uptake images at 4 h (SERT binding) and 24 h (DAT binding) p. i. Results: In PD bilateral reduction of striatal DAT binding (63-70%) was seen. The caudate ipsilateral to the clinically predominantly affected side showed relatively the least impairment. Significant correlations (r = -0.54 to -0.64) between DAT binding and Hoehn and Yahr stage, UPDRS-scores and duration of disease were found. In MSA DAT binding was less reduced (40-48%) targeting the putamen contralateral to the side of clinical predominance. Significantly lower SERT binding was observed in PD midbrain and MSA hypothalamus compared to controls – and in MSA relative to PD mesial frontal cortex. Conclusions: In advanced PD striatal DAT binding is markedly reduced with the least reduction in caudate ipsilateral to the clinically predominantly affected side. In moderate MSA with asymmetrical symptoms DAT dysfunction is predominant in the contralateral putamen, a pattern seen in early PD. The reduction of SERT in the midbrain area of PD patients suggests additional tegmental degeneration while in MSA the serotonergic system seems to be more generally affected.

Zusammenfassung

Ziele: Bestimmung der regionalen Verteilung der Dopamintransporter(DAT)-Dysfunktion bei fortgeschrittenem Morbus Parkinson (MP) und Korrelation der DAT-Bindung zur Symptomatik; Klärung der Bedeutung der DAT-Darstel-lung für die Differenzialdiagnose von MP und Multisystematrophie (MSA); Einschätzung und Vergleich der Serotonintransporter(SERT)-Bindung bei MP und MSA. Methoden: [¹²³I]ß-CIT-SPECT wurde bei 14 Patienten mit fort-geschrittenem MP, 10 mit mittelgradiger MSA und 20 Gesunden durchgeführt. Quotienten von spezifischer zu unspezifischer Bindung des Tracers (V₃‘‘) wurden durch ROI-Analysen der Tomogramme nach 4 h (SERT-Bindung) und 24 h (DAT Bindung) p. i. bestimmt. Ergebnisse: Bei MP fanden sich beidseits signifikante Reduktionen (63-70%) der striatalen DAT-Bindung. Im Nucleus caudatus ipsilateral zur klinisch hauptsächlich betroffenen Seite zeigte sich die geringste Minderung. Signifikante Korrelationen (r = -0,54 bis -0,64) zwischen DAT-Bindung und Hoehn-Yahr-Stadium, UPDRS-Score und Erkrankungsdauer wurden beobachtet. Bei MSA war die DAT-Bindung geringer reduziert (um 40-48%) – am deutlichsten im kontralateralen Putamen. Signifikant vermindert war die SERTBindung im Mittelhirn von MP- und Hypothalamus von MSA-Patienten gegenüber Gesunden, sowie im mesialen frontalen Kortex bei MSA im Vergleich zum MP. Schlussfolgerungen: Bei fortgeschrittenem MP ist die DAT Bin-dung im ipsilateral zur klinisch hauptsächlich betroffenen Seite gelegenen Caudatus relativ erhalten und im übrigen Striatum deutlich reduziert. Bei mittelgradiger MSA mit asymmetrischer Symptomatik findet sich wie beim frühen MP die deutlichste DAT-Dysfunktion im kontralateralen Putamen. Die Reduktion der SERT-Bindung im Mittelhirn bei MP lässt auf zusätzliche tegmentale Degeneration schließen, während bei MSA eher das serotonerge System insgesamt betroffen zu sein scheint.

Keywords

Dopamine transporter - serotonin transporter - Parkinson’s disease - multiple system atrophy - SPECT - beta-CIT

Schlüsselwörter

Dopamintransporter - Serotonintransporter - Morbus Parkinson - Multisystematrophie - SPECT - beta-CIT

^* Diese Arbeit ist Prof. Dr. Dr. h.c. Heinz Hundeshagen zum 75. Geburtstag gewidmet.

• References

• 1 Asenbaum S, Brücke T, Pirker W. et al. Imaging of dopamine transporters with iodine-123-beta-CIT and SPECT in Parkinson’s disease. J Nucl Med 1997; 38: 1-6.
• 2 Korf J, van Praag HM. The intravenous probenecid test: a possible aid in evaluation of the serotonin hypothesis on the pathogenesis of depressions. Psychopharmacologia 1970; 18: 129-32.
• 3 Bettin S, Kämpfer I, Seese A. et al. Striatale Aufnahme von I-123- -CIT und I-123-IBZM bei Patienten mit extrapyramidaler Symptomatik. Nuklearmedizin 1997; 36: 167-72.
• 4 Brooks DJ. PET studies on the early and differential diagnosis of Parkinson’s disease. Neurology 1993; 43 (Suppl. 06) S6-16.
• 5 Brooks DJ, Ibanez V, Sawle GV. et al. Differing patterns of striatal ¹⁸F-dopa uptake in Parkinson’s disease, multiple system atrophy, and progressive supranuclear palsy. Ann Neurol 1990; 28: 547-55.
• 6 Brücke T, Asenbaum S, Pirker W. et al. Measurement of the dopaminergic degeneration in Parkinson’s disease with [¹²³I] beta-CIT and SPECT. Correlation with clinical findings and comparison with multiple system atrophy and progressive supranuclear palsy. J Neural Transm Suppl 1997; 50: 9-24.
• 7 Brücke T, Kornhuber J, Angelberger P. et al. SPECT imaging of dopamine and serotonin transporters with [¹²³I]beta-CIT. Binding kinetics in the human brain. J Neural Transm Gen Sect 1993; 94: 137-46.
• 8 Burn DJ, Sawle GV, Brooks DJ. The differential diagnosis of Parkinson’s disease, multiple system atrophy, and Steele-Richardson-Olszewski syndrom: Discriminant analysis of striatal ¹⁸F-dopa PET data. J Neurol Neurosurg Psychiatr 1994; 57: 278-84.
• 9 Carroll FI, Rahman MA, Abraham P. et al. [¹²³I]3 -(4-Iodophenyl)tropan-2 -carboxylic acid methyl ester (RTI-55), a unique cocaine receptor ligand for imaging the dopamine and serotonin transporters in vivo. Med Chem Res 1991; 1: 289-94.
• 10 D’haenen H. Imaging the serotonergic system in depression. Eur Arch Psychiatry Clin Neurosci 2001; 251 (Suppl. 02) II76-80.
• 11 Fahn S, Elton RL. Members of the UPDRS development commitee.. Unified Parkinson’s Disease Rating Scale. In: Fahn S, Marsden CD, Calne DB. et al (eds). Recent developments in Parkinson’s disease. Florham Park, New Jersey: Macmillan; 1987. Vol 2: 293-304.
• 12 Fetoni V, Soliveri P, Monza D. et al. Affective symptoms in multiple system atrophy and Parkinson’s disease: response to levodopa therapy. J Neurol Neurosurg Psychiatry 1999; 66: 541-4.
• 13 Frost JJ, Rosier AJ, Reich SG. et al. Positron emission tomographic imaging of the dopamine transporter with ¹¹C-WIN 35,428 reveals marked declines in mild Parkinson’s disease. Ann Neurol 1993; 34: 423-31.
• 14 Gelb DJ, Oliver E, Gilman S. Diagnostic criteria for Parkinson disease. Arch Neurol 1999; 56: 33-9.
• 15 Gibb WR. Neuropathology of Parkinson’s disease and related syndromes. Neurol Clin 1992; 10: 361-76.
• 16 Goto S, Hirano A, Matsumoto S. Subdivisional involvement of nigrostriatal loop in idiopathic Parkinson’s disease and striatonigral degeneration. Ann Neurol 1989; 26: 766-70.
• 17 Green AI, Mooney JJ, Posener JA. et al. Mood disorders: Biochemical aspects. In: Kaplan HI, Sadock BJ. (eds). Textbook of Psychiatry. Baltimore: Williams and Wilkins; 1995. VI 1089-102.
• 18 Haapaniemi TH, Ahonen A, Torniainen P. et al. [¹²³I]beta-CIT SPECT demonstrates decreased brain dopamine and serotonin transporter levels in untreated Parkinsonian patients. Mov Disord 2001; 16: 124-30.
• 19 Halliday GM, Blumbergs PC, Cotton RG. et al. Loss of brainstem serotonin- and substance P-containing neurons in Parkinson’s disease. Brain Res 1990; 510: 104-7.
• 20 Hoehn MM, Yahr MD. Parkinsonism. Onset, progression and mortality. Neurology 1967; 17: 427-42.
• 21 Hornykiewicz O, Shannak K. Brain monoamines in progressive supranuclear palsy – comparison with idiopathic Parkinson’s disease. J Neural Transm Suppl 1994; 42: 219-27.
• 22 Huang WS, Lin SZ, Lin JC. et al. Evaluation of early-stage Parkinson’s disease with ^99mTcTRODAT-1 imaging. J Nucl Med 2001; 42: 1303-8.
• 23 Huber SJ, Chakeres DW, Paulson GW. et al. Magnetic resonance imaging in Parkinson’s disease. Arch Neurol 1990; 47: 735-7.
• 24 Ilgin N, Zubieta J, Reich SG. et al. PET imaging of the dopamine transporter in progressive supranuclear palsy and Parkinson’s disease. Neurology 1999; 52: 1221-6.
• 25 Jellinger K, Riederer P, Tomonaga M. Progressive supranuclear palsy: clinico-pathological and biochemical studies. J Neural Transm Suppl 1980; 16: 111-28.
• 26 Kim YJ, Ichise M, Ballinger JR. et al. Combination of dopamine transporter and D2 receptor SPECT in the diagnostic evaluation of PD, MSA, and PSP. Mov Disord 2002; 17: 303-12.
• 27 Kim SE, Lee WY, Choe YS. et al. SPECT measurement of iodine-123-beta-CIT binding to dopamine and serotonin transporters in Parkinson’s disease: correlation with symptom severity. Neurol Res 1999; 21: 255-61.
• 28 Kish SJ, Shannak K, Hornykiewicz O. Uneven pattern of dopamine loss in the striatum of patients with idiopathic Parkinson’s disease. Pathophysiologic and clinical implications. N Engl J Med 1988; 318: 876-80.
• 29 Kuikka JT, Tiihonen J, Bergstrom KA. et al. Imaging of serotonin and dopamine transporters in the living human brain. Eur J Nucl Med 1995; 22: 346-50.
• 30 Landwehrmeyer B, Palacios JM. Alterations of neurotransmitter receptors and neurotransmitter transporters in progressive supranuclear palsy. J Neural Transm Suppl 1994; 42: 229-46.
• 31 Laruelle M, Baldwin RM, Malison RT. et al. SPECT imaging of dopamine and serotonin transporters with [¹²³I]beta-CIT: pharmacological characterization of brain uptake in nonhuman primates. Synapse 1993; 13: 295-309.
• 32 Malison RT, Price LH, Berman R. et al. Reduced brain serotonin transporter availability in major depression as measured by [¹²³I]-2 beta-carbomethoxy-3 beta-(4-iodophenyl)tropane and single photon emission computed tomography. Biol Psychiatry 1998; 44: 1090-8.
• 33 Marek KL, Seibyl JP, Zoghbi SS. et al. [¹²³I] beta-CIT/SPECT imaging demonstrates bilateral loss of dopamine transporters in hemi-Parkinson’s disease. Neurology 1996; 46: 231-7.
• 34 Mayeux R, Stern Y, Sano M. et al. The relationship of serotonin to depression in Parkinson’s disease. Mov Disord 1988; 3: 237-44.
• 35 Menza MA, Palermo B, DiPaola R. et al. Depression and anxiety in Parkinson’s disease: possible effect of genetic variation in the serotonin transporter. J Geriatr Psychiatry Neurol 1999; 12: 49-52.
• 36 Messa C, Volonte MA, Fazio F. et al. Differential distribution of striatal [¹²³I]beta-CIT in Parkinson’s disease and progressive supranuclear palsy, evaluated with single-photon emission tomography. Eur J Nucl Med 1998; 25: 1270-6.
• 37 Mossner R, Schmitt A, Syagailo Y. et al. The serotonin transporter in Alzheimer’s and Parkinson’s disease. J Neural Transm Suppl 2000; 60: 345-50.
• 38 Murai T, Muller U, Werheid K. et al. In vivo evidence for differential association of striatal dopamine and midbrain serotonin systems with neuropsychiatric symptoms in Parkinson’s disease. J Neuropsychiatry Clin Neurosci 2001; 13: 222-8.
• 39 Neumeyer JL, Wang SY, Milius RA. et al. [¹²³I]-2 beta-carbomethoxy-3 beta-(4-iodophenyl) tropane: high-affinity SPECT radiotracer of monoamine reuptake sites in brain. J Med Chem 1991; 34: 3144-6.
• 40 Noe SE, Irimia SP, Pomares AEM. et al. Neuropsychiatric disorders in parkinson s disease. Rev Neurol 2001; 32: 676-81.
• 41 Pilo L, Ring H, Quinn N. et al. Depression in multiple system atrophy and in idiopathic Parkinson’s disease: a pilot comparative study. Biol Psychiatry 1996; 39: 803-7.
• 42 Pirker W, Asenbaum S, Bencsits G. et al. [¹²³I]beta-CIT SPECT in multiple system atrophy, progressive supranuclear palsy, and corticobasal degeneration. Mov Disord 2000; 15: 1158-67.
• 43 Polinsky RJ, Brown RT, Burns RS. et al. Low lumbar CSF levels of homovanillic acid and 5-hydroxyindoleacetic acid in multiple system atrophy with autonomic failure. J Neurol Neurosurg Psychiat 1988; 51: 914-9.
• 44 Rakshi JS, Uema T, Ito K. et al. Frontal, midbrain and striatal dopaminergic function in early and advanced Parkinson’s disease A 3D [¹⁸F]dopa-PET study. Brain 1999; 122: 1637-50.
• 45 Ransmayrl G, Seppi K, Donnemiller E. et al. Striatal dopamine transporter function in dementia with Lewy bodies and Parkinson’s disease. Eur J Nucl Med 2001; 28: 1523-8.
• 46 Seibyl JP, Marek KL, Quinlan D. et al. Decreased single-photon emission computed tomographic [¹²³I]beta-CIT striatal uptake correlates with symptom severity in Parkinson’s disease. Ann Neurol 1995; 38: 589-98.
• 47 Tedroff J, Aquilonius SM, Hartvig P. et al. Monoamine re-uptake sites in the human brain evaluated in vivo by means of ¹¹C-nomifensine and positron emission tomography: the effects of age and Parkinson’s disease. Acta Neurol Scand 1988; 77: 192-201.
• 48 Tissingh G, Booij J, Bergmans P. et al. Iodine-123-N-omega-fluoropropyl-2beta-carbomethoxy-3beta-(4-iod ophenyl)tropane SPECT in healthy controls and early-stage, drug-naive Parkinson’s disease. J Nucl Med 1998; 39: 1143-8.
• 49 Varrone A, Marek KL, Jennings D. et al. [¹²³I]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.
• 50 Wenning GK, Ben-Shlomo Y, Magalhaes M. et al. Clinicopathological study of 35 cases of multiple system atrophy. J Neurol Neurosurg Psychiat 1995; 58: 160-6.
• 51 Wenning GK, Seppi K, Tison F. et al. A novel grading scale for striatonigral degeneration (multiple system atrophy). J Neural Transm 2002; 109: 307-20.
• 52 Willeit M, Praschak-Rieder N, Neumeister A. et al. [¹²³I]-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.