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Dopamine Transporters Decrease with Age 5. GonzalezCF.MoretJ.Balloonocclusionofthecarotidarterypriortosurgeryforneck 15. Momma F, Wang AD, Symon L. Effects of temporary arterial occlusion on somato tumors. AJNR 1990;11:649 —652. sensory evoked responses in aneurysm surgery. Surg Neurol 1987:27:343—352. 6. PetermanSB,TaylorA Jr.HoffmanJCJr.Improveddetectionof cerebralhypoper 16. Kelly JJ, Callow AD, O'Donnell TF, et al. Failure of carotid stump pressures. Its fusion with internal carotid balloon test occlusion and W@@Tc@HMPAOcerebral incidence as a predictor for a temporary shunt during carotid endarterectomy. Arch perfusion SPECT imaging. AJNR 1991;l2:l035—104I. Surg 1979;ll4:1361—l366. 7. Monsein LH, Jeffrey PJ, van Heerden, et al. Assessing adequacy of collateral 17. Holmes AE, James IM, Wise CC. Observations on distal intravascular pressure circulation during balloon test occlusion of the internal carotid artery with @“Tc changes and cerebral blood flow after common carotid artery ligation in man. J Neurol HMPAO SPEd. AJNR 1991;12:1045-1051. NeurosurgPsychiatry 1971:34:78—81. 8. Eskridge JM. The challenge of carotid occlusion. AJNR 1991;I2:1053—1054. 18. Feaster SH, Powers A, Laws ER, et al. Transcranial doppler US as an alternative to 9. Nishioka H. Report on the cooperative study of intracranial aneuiysm and subarach angiography and balloon test occlusion in estimating risk of carotid occlusion noid hemorrhage. Section VIII, Part I. Results of the treatment of intracranial [Abstract]. Radiology I990; 177(p):28 1. aneurysms by occlusion of the carotid artery in the neck. J Neurosurg 1966;24:660— 19. Erba SM, Horton JA, Latchaw RE, et al. Balloon test occlusion ofthe intemal carotid 682. artery with stable xenon/CT cerebral blood flow imaging. AJNR l988;9:533—538. 10. Matas R. Testing the efficiency of the collateral circulation as a preliminary to the 20. Johnson DW, Stringer WA, Marks MP, et al. Stable xenon CT cerebral blood flow occlusion ofthe great surgical arteries. Ann Surg 1911;53:l—43. imaging: rationale for and role in clinical decision making. AJNR 199l;12:201—203. I I. Fox AJ, Vinuela F, Pelz DM, et al. Use of detachableballoonsfor proximal artery 21. Lenzi GL, Frackowiak RSJ, Jones T. Cerebral oxygen metabolism and blood flow in occlusion in the treatment of unclippable cerebral aneurysms. J Neurosurg 1987;66: human cerebral ischemic infarction. J Cereb Blood Plow Metab 1982;2:321—335. 40—46. 22. Matsuda H, Higashi 5, Ash IN, et al. Evaluation of cerebral collateral circulation by 12. Jeifreys RV, Holmes AE. Common carotid ligation for the treatment of ruptured 99mTcHMpAO brain SPECT during Matas test: report of three cases. J Nuci Med posterior communicating aneurysm. J NeurolNeurosurg Psychiatry 197 1:34:576—579. l988;29: I724—I729. 13. Leech PJ, Miller JD, Fitch W, et al. Cerebral blood flow, internal carotid artery 23. Sharp PF, Smith FW, Gemmell HG, et al. Technetium-99m-HMPAO stereoisomers as pressure and the EEG as a guide to the safety of carotid ligation. J Neurol Neurosurg potential agents for imaging regional cerebral blood flow: human volunteer studies. J Psychiatry l974;37:854—862. Nuc!Med 1986;27:17l—177. 14. Trojaborg W, Boysen 0. Relation between EECI, regional cerebral blood flow and 24. Neimckx RD, Canning LR, Piper IM, et al. Technetium-99m d,l-HMPAO: a new intemal carotid artery pressure during the carotid endarterectomy. Electroencephalogr radiopharmaceutical for SPECT imaging of regional cerebral blood perfusion. J Nuc! ClinNeuropkvsiol1973;34:61—69. Med 1987;28:191—202. Dopamine Transporters Decrease with Age Nora D. Volkow, Yu-Shin Ding, Joanna S. Fowler, Gene-Jack Wang, Jean Logan, S. John Gatley, Robert Hitzemann, Gwenn Smith, Suzanne D. Fields and Ruben Gur Medical and Chemistry Departments Brookhaven National Laboratory, Upton, New York; Departments ofPsychiatry and Medicine, Division of Geriatrics, SUNY-Stony Brook, Stony Brook, New York; Department ofPsychiatry, New York University, New York, New York; and Department ofPsychiatry, University ofPennsylvania, Philadelphia, Pennsylvania the neurochemical changes accompanying normal aging. Aging Postmortem studies have documented degenerationof dopamine is associated with changes in several neurotransmitters (2) as cells with age, but the changes that occur in healthyaging indMd ualsis lessclear.The purposeof this studywas to evaluatethe well as changes in specific motor, cognitive and emotional extent to which age-induced changes in doparnine transporters behaviors (3). The dopaminergic system appears to be among occur in subjects with no evidence of motor impairment. Methods the most age-sensitive neurotransmitters (4). Of the behavioral Weevaluated23right-handedhealthyvolunteers(agerange20-74 changes associated with aging, the most conspicuous are those yr) usingPETand r1c][email protected] ratioof the related to motonc function. For example, aging is associated distributionvolumefor r1c1d-th@-mefh@be@*istein striatumto with a higher frequency of dyskinesias (5—6)and of mild that in cerebellumwas usedas modelparameterfordopamine Parkinson-like motor changes such as rigidity (7). Some of transporteravailability(Bmax/Kd+ 1).Results Dopaminetrans these motoric changes may reflect an age related decline in porteravalIabift@,wassignificantlylowerin subjects>40 yr of age thaninthose<40 yr.Estimatesof dopaminetransporteravailability nigrostriatal dopaminergic function (8). showed a signfficant negative correlation with age both for the Studies in animals as well as postmortem human brain putamen (r = —0.72,p < 0.0001)and the caudate (r = —0.74,p < studies, have in general documented a decline in brain dopa 0.0001).Doparninetransporter availat@litywas higherin the leftthan mine activity with aging (9, 10). Recently, imaging techniques in the rightputamenbut did not differbetweenthe leftand right such as PET and SPECT have enabled the measurement of caudate. Conclusion: This study documents a 6.6% decreaseper changes in dopamine parameters as a function of age in living decade of life in striatal dopamine transporters of healthy volun human subjects. Most of these studies have focused on dopa tears. mine receptors and have documented a decrease in D2 and Dl Key Words PET; dopamine transporters; degeneration receptor density with aging (11—18).Changes in dopamine J NucIMed1996;37554.-559 receptors, however, predominantly reflect changes in postsyn aptic elements presumably GABAergic, muscarmnicand gluta AccordingtoprojectionsbytheU.S.BureauoftheCensus,matergic neurons and not changes in dopaminergic neurons. the number of individuals 65 yr and older will more than double Few studies have been conducted on age-related changes in by the middle ofthe next century to nearly 79 million. Whereas dopamine neurons in living human subjects. Age changes in the about 1 in 8 Americans were elderly in 1990, about 1 in 5 could dopamine neurons of living human subjects have been studied, be elderly in the year 2030 (1 ). This progressive increase in the using PET and SPECT tracers, to measure dopamine metabo elderly population places a sense of urgency on understanding lism and dopamine transporter sites. Studies using [18F]fluoro DOPA to measure dopamine metabolism have been inconclu sive documenting reduced uptake (19) as well as no changes ReceivedFeb.15,1995;revisionacceptedJul.30,1995. Forcorrespondenceor reprintscontact Nora D. volkow, MD, Med@alDepartment (20,21). Preliminarystudiesusing @l1C]nomifensine(22), BrookhavenNationalLaboratory,Upton,NY11973. [1 ‘C]cocaine (23 ) and [‘23I]@3-CIT (24) as ligands for the 554 THEJOURNALOFNUCLEARMEDICINE•Vol. 37 •No. 4 •April1996 dopamine transporters have documented decreases in dopamine fractions (2 X 5 ml deionized water followed by 2 X 50% transporter sites with aging whereas studies using [‘‘C]WIN35 methanol). The radioactivity remaining on the cartridge repre 428 have not (25). sented unchanged tracer. Solid phase analysis was validated by This report shows the effects ofage on dopamine transporters HPLC analysis of plasma. The stability of @l‘C]d-threo-methyl in 23 normal healthy subjects using [‘‘C]d-threo-methylpheni phenidate to racemization was assessed using a chiral HPLC date, a new PET ligand with a higher sensitivity and specificity system described previously (26). than that of [‘1C]nomifensine and [l 1C]cocaine. We proposed Image An@ [I ‘C]d-threo-methylphenidate, the more active enantiomer of Regions of interest (ROls) were drawn on the individual's methylphenidate, as a PET ligand for the dopamine transporter averaged emission scan obtained by averaging the activity from (26). Carbon-i i-d-threo-methylphenidate binding is inhibited 10—84mm after injection of the tracer. ROIs for striatum(caudate by drugs that bind to the dopamine transporter, but not by drugs and putamen) and cerebellum from each subject's averaged images that inhibit the norepinephrine and the serotonin transporters were then projected to his/her corresponding dynamic emission indicating its selectivity for the dopamine transporter (26). scans. ROIs were obtained in two planes and left and right regions Carbon-i i-d-threo methylphenidate binding in the human brain were obtained in each plane. A weighted averaged value was then is reversible, highly reproducible and saturable and its kinetics obtained for the left and right caudate, the left and right putamen are ideally suited for quantitation (27). The results from this and the cerebellum. To compare the current results with
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