An overview is presented of positron computed tomography: its advantages over single photon emission tomography, its use in metabolic studies of the heart and chemical investigation of the brain, and future trends. (ACR

Kuhl, D.E.

Phelps, M.E.

Schelbert, H.R.

Schelbert, H. R.

Phelps, M. E.

Kuhl, D. E.

UNT Digital Library

-LABORATORY OF NUCLEAR MEDICINE AND RADIATION BIOLOGY ". . *I .. * ,...,. * .."& '. 900 VETERAN AVENUE UNIVERSITY OF :ALIFORNIA, LCS ANGELES, CALIFORNIA 90024 AND DEPARTMENT OF RADIOLOGICAL SCIENCES . 1  UCLA SCHOOL OF MEDICINE, LOS ANGELES, CALIFORNIA 90024 .These s t u d i e s  were supported by Contract #DE-AM03-76-SF00012 between t h e  U.S. i Department of Energy and t h e  Universi ty  of Ca l i fo rn ia  ~ This conference paper was submitted 7/25/80 t o  t h e  Proceedings of  t h e  18th.  In t e rna t iona l  Annual Meeting of  t h e  Society of Nuclear Medicine t o  be held September 9-12, i n  Nzrnberg, West Germany, 'Prepared f o r  t h e  U.S. Department of En,ergy under Contract #DE-AMO3-76-SF00012 POSITRON COMPUTED TOMOGRAPHY: CURRENT STATE, CLINICAL RESULTS AND F W R E  TRENDS Heinrich R. Schelbert,.M.D., Michael E. Phelps, Ph.D. and David E. Kuhl, M . D .  ' I  DISCLAIMER  This report was prepared as an account of work sponsored by an agency of the United States Government.  Neither the United States Government nor any agency Thereof, nor any of their employees, makes any warranty, express or implied, or assumes any legal liability or responsibility for the accuracy, completeness, or usefulness of any information, apparatus, product, or process disclosed, or represents that its use would not infringe privately owned rights.  Reference herein to any specific commercial product, process, or service by trade name, trademark, manufacturer, or otherwise does not necessarily constitute or imply its endorsement, recommendation, or favoring by the United States Government or any agency thereof.  The views and opinions of authors expressed herein do not necessarily state or reflect those of the United States Government or any agency thereof. DISCLAIMER  Portions of this document may be illegible in electronic image products.  Images are produced from the best available original document.  Divisioa of Nuclear Medicine, UCLA School of Medicine, and The Laboratory of Nuclear Medicine and Radiation Biology, University of California at Los Angeles, California, USA Positron Computed Tomography: Current State, Clinical Results and Future Trends : Heinrich R Schelbert, Michael E Phelps and David.E Kuhl 1 Emission computed tomography has become an attractive new means for the nontraumatic study of physiologic processs. Introduced in 1963 (l) this imaging modality overcomes many of the limitations inherent to conventional imaging. Ideally, emission tomography should permit external visualization of the three dimensional distribution of radioactive tracers in organs in form of tomographic images with a resolution that is independent of depth, represent the local distribution of radioactive tracers quantitatively and, hence, provide a capability comparable to in vitro counting of tissue samples or autoradiography (2). For studies of the brain these criterias can be largely met by single photon emission tomography(3) while cardiac studies with -this imaging device have been limited by a lack of satisfactory correction for photon attenuation and by the depth dependent resolution (4). BY contrast, positrug computed tomography (PCT) permits direct measurements of and correction for photon attenution on the emi.ssion images (2 ) .  Moreover, due to _ -  ~ I -  tk. +LectrLcz& cclkim:%tion the resolution of PCT images is depth independent. Thus, poaitron emissim computed tomography is at present superic!? for studies of the heart. In addition, positron emitting radiopharmaceuticals have become available that trace metabolic pathways In a known and well defineable manner and allow, through quantitative imaging, the nontraumatic measurement of local organ function. On the other hand, a drawback for PCT is the need for an on site cyclotron and the relatively high zost. ' Positron emitting indicators 1 Design of single photon emitting .radiopharmaceuticals that trace physiologic processes has been difficult in the past. Labeling of Tc-99mB I- 123 or 1-131 to physiologically active substances often modified their t i n e t i c s  so that they no longer were useful for studying a specific physiologic process. By contrast, positron emitting 0-15, C-11, N-13 or F-18 :an be labeled to metabolically active substrates such as glucose, free fatty i acids (FFA) or amino acids without significantly altering their biologic properties. C-11 palmitate as a primary substrate of myocardial energy metaboldsm for example has permitted the study of regional myocardial FFA uptake, its subsequent breakdown through @-oxidation and storage in form of triglycerides or neutral lipids. This has been possible because of the relatively slow clearance of this substrate from myocardium. Evaluation of carbohydrate metabolism may however be more difficult. Although glucose can be labeled with C-11, it is rapidly metabolized in tissues. The tissue C-11 activity recorded with PCT therefore represents a complex distribution of C-11 ~ - ~ , t a b o ~ ~ ~ c _ _ ~ ~ ~ ~ ~ ~ ~ ~ ~ a ~ e ~  thac changes with time and is difficult to use for quantitative measurementc of glucose metabolism. -- - This emphasizes the need for substrate analogs that trace metabolic pathways or representative steps in a known and well-defineable manner. F-18 2-fluoro 2-deoxy-glucose (FDG) exemplifies such a substrate analog. Sokoloff et a1 had used initially C-14 labeled deoxyglucose to measure local cerebral glucose metabolism in rats by autoradiography. Substitution of the 2-deoxy group b3 an F-18 atom(3) permitted use of this analog for PCT imaging of the brain and heart(7 S 8 s 9 ) .  FDG traces the transcapillary and transmembraneous exchange of exogeneous glucose and the initial, hexokinase mediated phosphorylation of glucose to glucose -6-phosphate. Since FDG-6-phosphate is not a wibstrate for glycolysis, the pentose shunt or for glycogen storage, it becomes metabolically trapped. The tissue concentrations can be quantified externally by PCT and are a measure of local glucose utilization rates. At near steady state conditions, FDG tissue concentrations reflect the amount of phosphorylated FDG which is related t o  the input function, the rate of phospho-i-ylation, and the time after administration. Physiologic modeling I Measurement of local metabolic rates requires physiologic modeling of the tracer kinetics. This entails mathematical description of the kinetics of a given tracer with the aid of a physiologic model. Two types of physiologic models are currently in use: The steady state, multicompartment model and the unidirectional transport model. I n  the latter model, the radioindicator is transported from the vascular compartment into the cell unidirectionally where it is,subsequently fixed or metabolically trapped. I n  the former model, metabolic rates are either measured using labeled compounds which equilibrate between.physiologic compartments and accumulate i n  t i s s u e  i n  proport ion t o  the  rate of t h e  metabolic process o r  which clear as metabolic breakdown products from t h e  t i s s u e .  The rates of these processes  are est imated from the  a r t e r i a l  plasma concentrat ion of t he  labeled s u b s t r a t e  - t he  input  func t ion  - and the  t i s s u e i  r a d i o a c t i v i t y  concent ra t ion  as a func t ion  of t i m e .  I f  t h e  labe led  product of metabolism is  trapped i n  the  t i s s u e  the  model can be s impl i f i ed  and r equ i r e s  only a s i n g l e  measurement of t h e  t i s s u e  r a d i o a c t i v i t y  concent ra t ion  if t he  average values  of the  r a t e  cons tan ts  of the  model are known. If the  metabolic products  of t he  labe led  s u b s t r a t e  r ap id ly  clear from t i s s u e  then the  t i s sue '8concen t r a t ions  must be measured as a func t ion  of rime and t h e  model becomes more complex. The la t te r  approach a p p l i e s  t o  the  s tudy of myocardial FFA metabolism wi th  (2-11 p a l m i t a t e  whereas the  s impl i f i ed  s teady  state model can be employed wi th  FDG. S?Loloff ' s  o r i g i n a l  model was adopted t o  FDG (' and, subsequently modified (lo) and walidated i n  our labora tory  ('I). The k i n e t i c s  of FDG are expressed by a th ree  compartmental model with a vascular ,  ex t ravascular  and metabolic compartment. Exchange between compartments is descr ibed by f i r s t  o rder  k i n e t i c  rate cons t an t s  t h a t  c h a r a c t e r i z e  t h e  forward and r eve r se  t r anspor t  of FDG ac ross  the  c a p i l l a r y  and cel l  membranes and the  enzyme mediated rates of phosphorylation and dephosphorylation. The rate cons tan ts  and the  physiologic  model are entered i n t o  t h e  PCT system computer so t h a t  r eg iona l  metabolic rates can be measured semiautomatically by t r a ined  technic ians  from t h e  images of reg iona l  t i s s u e  FDG concent ra t ions ,  serial  a r te r ia l  plasma FDG and plasma glucose.  C l i n i c a l  Resul t s  To da te ,  sys temat ic  i n v e s t i g a t i o n s ' w i t h  PCT have been performed mainly i n  the  b r a i n  and hea r t .  . I n i t i a l  experience wi th  PCT of the  b ra in  has been very encourkging and suggests  an important f u t u r e  r o l e  of PCT i n  t h e  c l i n i c .  Kuhl (12) demonstrated - l o c a l  func t iona l  abnormal i t ies  wlth FDG and Ne13 e t  a1 amcmi-a*4.-.~l y t i e n t b  4 i t h  z t rnkes .  Abnormalit ies de tec ted  by PCT c o r r e l a t e d  .3r i- *I- . f a r  b e t t e r  with the  clinical symptoma:ology.than s t r u c t u r a l  abnormal i t ies  seen on thq* X-ray CT images. Not only d i d  PCT d e l i n e a t e  metabolic a l t e r a t i o n s  i n  bra in  segments a f f e c t e d '  d i r e c t l y  by . t h e  ischemic event but a l s o  i n  s t r u c t u r a l l y  i n t a c t  t i s e u e s  t h a t  were a f f e c t e d  secondar i ly  by d i s r u p t i o n  of neuron tracts. I n  ep i l epsy ,  Kuhl e t  a1 (I3)  demonstrated reduct ions i n  glucose metabolism i n  b ra in  regions which marked degenerat ive changes on h i s t o l o g i c  exmination of s u r g i c a l  specimens. Seizure a c t i v i t y  provoked i n  these  segments s t r i k i n g  inc reases  i n  f low and glucose metabolism. Phelps et a1 (14) demonstrated the  p o s s i b i l i t y  t o  quant i fy  reg iona l  metabolic responses t o  v i s u a l  s t imu la t ion  i n  man. The metabolic a c t i v i t y  of t he  v i s u a l  co r t ex  was found t o  progress ive ly  inc rease  as the  v i s u a l  scene became more complex w i t h  a maximuu inc rease  by a f a c t o r  of two. These s t u d i e s  demonstrate t he  unique c a p a b i l i t y  of PCT t o  develop a b e t t e r  understanding of l o c a l  c e r e b r a l  func t ion  i n  h e a l t h  and d isease .  S imi la r  progress  has been made i n  the  hea r t  (15). Unlike the  b r a i n  which almost exc lus ive ly  uses  glucose as i t s  'energy subs t r a t e ,  the  heart uses  FFA, glucose,  lactate,  and ketone bodies  t o  varying degrees depending upon the  s ta te  of supply and demand. This complicates t h e  noninvasive study of r eg iona l  myocardial metabolism. Secondly, ex tens ive  n e u r o s c i e n t i f i c  research  has provided a framework f o r  metabolic s t u d i e s  with PCT which does not ex is t  t o  th; same degree f o r  t he  hea r t .  Nevertheless ,  w e  have demonstrated t h a t  d e s p i t e  t he  ob jec t  s i z e  r e l a t e d  loss i n  count recovery reported by Hoffman e t  (I6) t r u e  m y o k r i i a l  i n d i c a t o r  t l s s u e  concent ra t ions  can be accu ra t e ly  measured once the  thickriess of t he  r e l a t i v e l y  t h i n  myocardium i s  known . This also permi t s  measurements of nyocard ia l  w a l l  th ickening as an index of r eg iona l  mechanical funct ion.  S imi la r ly ,  t he  microsphere technique f o r  myocardial blood flow (MBF) measurements i n  animals was adopted to  the  noninvasive measurement of r eg iona l  MBF by PCT (I7). have used the  generator  produced Rubidium-82 as d i f f u s i b l e  flow i n d i c a t o r ,  we have cha rac t e r i zed  N-13 ammonia as an i n d i c a t o r  of MBF t h a t  is s u i t a b l e  for (17) ?! _ .  -A*--., ..- i (18) While Budinger e t  a1 pcT( 17 1 . PCT toge ther  with N-13 ammonia i n j e c t e d  during pharmacologically induced coronary hyperemia has allowed de tec t ion  of mild coronary s tenoses  i n  experi  icental  animals (I9). These s t u d i e s  have been extended t o  man and suggest  t h a t  coronary s tenoses  can be de tec ted  w i t h ,  a similar degree of iccuracy (*l). Not only does t h i s  approach appear more . s e n s i t i v e  than  T1-201 3tress imaging but a l s o  super ior  f o r  de t ec t ing  mul t ivease l  involvement. The k i n e t i c s  of C - 1 1  palmitate i n  myocardium have been ex tens ive ly  ?valuated.  T h i s , m e t a b o l i c  r ad io ind ica to r  has been used f o r  the  s tudy of nyocardial  metabol ic  i n t e g r i t y  i n  animals and p a t i e n t s  with acu te  myocardial i n f a r c t i ~ n ( ~ - ~ ) .  Hypothesizing t h a t  myocardial ischemia is assoc ia t ed  with anaerobic  g lyco lys i s  w e  evaluated the  p o s s i b i l i t y  of demonstrating noninvasively metabol ic  consequences of acu te  myocardial ischemia. I n  the  exper iyenta l  animal uptake of exogeneous glucose i n  the  ischemic segment w a s  e i t h e r  increased  or in excess  of f low and, hence, oxygen a v a i l a b i l i t y  . Similar observat ions were made i n  man and lead us t o  conclude t h a t  t he  acc~tePj++=c5..b,dc myic:hrdt?!. segment r e s o r t s  t o  glucose as i t s  energy s u b s t r a t e  which probabl!: is metaboliLed through r e s i d u a l  ox ida t ive  capac i ty  and/or ' 4  anaerobic  g lyco lys i s .  S imi l a r ly  encouraging are observat ions i n  ch i ld ren  wi th  segmental myocardiopathies, where the  i n i t i a l  de fec t  appears  l o c a l i z e d  t o  c e l l u l a r  metabolism r a t h e r .  than the  vascular  supply (SCHELBERT, unpublished da ta) .  Future  Trends (24) I .  r'' , During t h e  p a s t  years ,  PCT has developed i n t o  a powerful and unique means f o r  t h e  i n  vivo s tudy of organ physiology. The observat ions i n  c e r e b r a l  d i s o r d e r s  s t rong ly  suggest a p o t e n t i a l l y  important r o l e  f o r  PCT. Current  e f f o r t s  focusing on the  development o r  testing of labe led  l igands  f o r  s tudying neuroreceptors  w i l l  provide a d d i t i o n a l  i n s i g h t s  i n t o  the  c e r e b r a l  physiology and perhaps become use fu l  i n  eva lua t ing  degenerat ive d i so rde r s  and p s y c h i a t r i c  problems. PCT f u r t h e r  appears promising f o r  the  s tudy of each aspec t  of ca rd iac  perforrssince, i.e. mechanical funct ion,  MBF and metabolism. Because these  measurements can be obtained i n  a s i n g l e  s e t t i n g ,  i t  is conceiveable t h a t  t he  metabolic l i n k  between blood flow and mechanical func t ion  can be es tab l i shed .  Moreover, i f  i t  becomes poss ib l e  t o  i d e n t i f y  r eg iona l  derangements i n  metabolism as a consequence of ischemia and t h e i r  s i g n i f i c a n c e  regarding ce l l  v i a b i l i t y ,  then PCT may become u s e f u l  f o r  i d e n t i f y i n g  ischemic and p o t e n t i a l l y  salvageable  myocardium, f o r  t e s t i n g  the  e f f ec t iveness  of t he rapeu t i c  i n t e rven t ions  and perhaps t o  develop new treatment  modal i t ies .  To date, only i n d i c a t o r s  of FFA and carbohydrate metabolism have been evaluated. Considering t h e  complexi t ies  of metabol ic  derangements i n  acu te  nyocardial  ischemia, l abe led  metabolic in te rmedia tes  or t h e i r  analogs and nmino a c i d s  may become u s e f u l  i n  t h e  f u t u r e  i n  de f in ing  more s p e c i f i c  a spec t s  3 f  metabolic a l t e r a t i o n s .  Ol)viously, f u t u r e  developments w i l l  inc lude  improvement i n  c u r r e n t  instrumentation. One of the major limitations of PCT has been the need for on-site production of positron emitters. Significant progress is being made in developing small, inexpensive and reliable accelerators that can be used by technologists in a generatorelike fashion. It also will be necessary to reduce indicator labeling to a state where it can be performed i n  a "kit like" manner. Improvements in imaging equipment are also under way. Design of more efficient, multislice tomographs with higher efficiencies and improved spatial resolution is in progress. This should provide. statistically improved imaging with greater anatomical detail acquired at less patient and personnel time. It would seem to us that these improvements in instrumentation and radiopharmaceuticals will permit a wider, more convenient and less expensive applicability of E'CT to clinical studies. Despite these improvements it appears that PCT will remain limited to major medical institutions. Yet it seems to us that techniques developed with PCT for the study of local organ metabolism may provide the framework and eventually be adopted to the less costly and widely available emission tomography with single photon emitters. (Supported by DOE contract #DE-AM03-76-SF00012) REFERENCES (1) KUHL and EDWARDS:Radiol 80:653, 1963; (2) PHELPS:Sem Nucl Med 7:337, 1977; (3) KUHL et a1:Radiol 121:405, 1976; (4) BUD1NGER:J Nucl Med 21:579, 1980; (5) SOKOLOFF et al:J Neurchem 28:897, 1976; (6) ID0 et al: J Org Chem 42:2341, 1977; (7) REIVICH et al: Act Neur Scand 56, Suppl. 64, 190, 977; (8) KUHL et al: Acta Neur Scand 56 Suppl 64. 192, 1977; (9) PHELPS et al: J Nucl Med 19:1311, 1978; (10) HUANG et al, Am J Physiol 238:E69, 1980; (11) PHELPS et al: Ann Neurol 6:371, 1979; (12) KUHL et al: Ann Neurol 8:47, 1980; (13) KUHL et al: Ann Neurol (in press); (14) PHEXPS et al: Science (in press; (15) ~IZ~ELY~H'S-.~~ ..-bJ i' %i- 2 H~.-r,l  Mad 5:209, 1980; (16) HOFFMAN et al: J Comp 4ssist Tomogr 3:299, 1979; (17) WISENKERG et al: (In press); (18) BUDINGER et nl: A m d  Cardiol 45:399, 1980 (abstract); (19) SCHELBERT et al: Am J Cardiol $3:209, 1979; (20) GOULD e t  al: Am J Cardiol 43:200, 1979; (21) SCIfELBERT et 31: Circ 59/60, Suppl II:60, 1979 (abstract); (22) WEISS et al: Circulation 55:66, 1977; (23) TER-POGOSSIAN et al: Circulation 61:242, 1980; (24) SCHELBERT et al: J Nucl Med 21:P90, 1980. ?or Contact IR SCHELBERT MD, Division of Nuclear Medicine, UCLA School of Medicine, Los ingeles, CA 90024. - 

Positron computed tomography: current state, clinical results and future trends

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