1983 animal studies using gd-dtpa weinman

8/2/2019 1983 Animal Studies Using Gd-DTPA WEINMAN

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62 5

Con tras t-E nhanced NMRImag ing : An im a l S tud ies U s ingG ado lin ium DTPA Com p lex

Robe rt C . B ra sch1H anns-Joach im W ein rnann2

G eorge E . W esbey1

Rece ived Ju ly 7 , 1 98 3 ; a cce p te d a fte r rev is io nNo vem ber 14 , 1 98 3 .

T h is w o rk w as sup po rte d in p a r t by a g ran t fromthe Na tio na l Ins titu te o f A rth ritis , D ia be tes , D iges -tiv e a nd K idn ey D ise ase s, AO l AM 31 937 .

1 Depa rtm en t o f R ad io lo gy , U n ive rs ity o f C alifo r -ni a Schoo l o f M ed ic ine , Sa n F ra nc isc o , C A 9414 3 .Ad d re ss re p rin t re qu ests to A . C . B ra sch (M -3 97 ).

2 Resea r c h La bo ra to rie s o f S ch e r ing . D -1 0 00Ber l in 65 , Ge rman y .AJR 1 42 :62 5 -6 30 , M arch 1 9840 36 1 - 80 3X /8 4/1 4 23 -0 62 5to Ame r i c a n Roen tge n Ra y Soc ie ty

G ado lin ium (G d )-D TPA com p le x w as assessed as a nuc lea r m agne tic re sonance(NMR ) con tras t-enhanc ing agen t b y expe rim en ta lly im ag ing norm al and d iseased an i-m a ls . A fte r in trav enous in je c tio n , G d -D TPA , a s trong ly pa ram agnet ic com p lex by v irtu eo f unpa ired e le c trons , w as rap id ly e xc re ted in to th e u r in e o f ra ts , p roduc ing an eas ilyobse rv ab le con tra s t enhancem en t on NM R im ages in k idney pa renchym a and u r in e .S p in -echo in tens ity o f u rin e w ith in th e rena l pe lv is in c re ased from 2263 to 4414 un its ;in tens ity o f rena l pa renchym a inc reased from 2901 to 3893 a fte r adm in is tra tion o f 0. 1m m o l/kg G d -DTPA . S te rile so ft-tis sue abscesses dem ons tra ted an obv ious r im p atte rno f enhancem en t. A fo cus o f rad ia tio n -in duced b ra in dam age in a can in e m ode l w as on lyfa in tly d e te c tab le on sp in -ech o NM R im ages be fo re con tra s t adm in is tra tio n ; a fte r 0 .5m m o l/kg G d -D iVA adm in is tra tio n , th e les ion in tens ity in c reased from 3867 to 5590 . Incom pa rison , th e no rm al b ra in w ith an in tac t b lood -b ra in ba rr ie r rem a in ed unchanged inNMR charac te riza tio n . G d -D TPA is a p rom is ing new NMR con tras t enhance r fo r th ec lin ica l as sessm en t o f rena l funct io n , o f in flamm a to ry les ions , and o f fo ca l d is rup tion ofth e b lood -b ra in bam er.

Io ns and m o lecu le s con ta in ing unpa ired e le c trons dem onstra te a pa ram agne ticbehav io r w hen p la ced in an ex te rna l m agne tic fie ld . S trong ly pa ram agne tic sub -s tances a re po ten tia lly u se fu l a s con tra s t-enhanc ing agen ts fo r nuc lear m agne ticre sonance (NM R ) im ag ing because they has ten re la xa tion ra te s o f p ro tons in the irm ic ro chem ica l env ironm en t; T i and T2 va lues a re sho rtened [1 -5 ].

G ado lin ium ions (G d3 from the lan than ide se rie s o f ra re -ea rth e lem en ts con ta inseven unpa ired e le c trons in the 4 -f e le c tron o rb ita ls , a pos itio n w e ll p ro te c ted fromchem ica l in te ra c tions w ith o the r a tom s . T hese e le c trons p rov ide gado lin ium w iths trong pa ram agne tic p rope rtie s [6 ]. G d3 can be che la ted w ith d ie th y l-am ine triam ine pen ta a ce tic a c id (D TPA ) to fo rm a s ta b le c om p lex (G d-DTPA ) w ith afo rm a tion cons tan t o f i 0 2 2 2 3 [7 ]. The m eg lum ine sa lt o f G d -DTPA a fte r in tra venousadm in is tra tion is rap id ly excre ted in to the u r ine w ith a sm a ll p ropo rtion appea ringin fe ces . T he pha rm aco log ic p ropertie s o f G d-D TPA inc lud ing s tab ility , pha rm aco -k ine tic s , and to le rance a re described in the accom pany ing a rtic le [4 ]; a ll th esefac to rs fa vo r the fu rthe r in ves tiga tion o f G d -D TP A as an NM R con tra s t agen t.

W e desc ribe im ag ing expe rim en ts te s ting G d -D TP A as an in tra venous con tra s tagen t fo r p ro ton NM R im ag ing in an im a ls . The ab ility o f G d-D TPA to contra s t-enhance no rm a lly func tion ing k idneys was s tud ied in ra ts . The po ten tia l to a lte r thes ign a l in te n s ity o f ed em ato us in flamm ato ry le s ion s o f the so ft t is sue s wa s s tu d iedin ra ts and a dog . T he u tility o f G d -DTPA to iden tify fo ca l d is rup tion o f the b lood -b ra in b a rrie r w a s in ves tig a te d in a dog w ith fo ca l ra d ia tion -ind uced dam age . O u rpu rpose w as to es tim a te the po ten tia l c lin ica l u til ity o f G d -D TPA -enhanced NM Rimag ing .


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62 6 BRASCH E T AL . A JR :14 2, M arch 1984

M ate ria ls and M e thodsN MR Im ag in g

NM R sp in -e ch o (SE )-in ten s ity im age s w ere ob ta ine d on a 0 .3 5 -Tres is tiv e NM A un it p rev io us ly d e sc ribe d [8 ]. T h e use fu l a pe rtu re fo rim a g in g wa s 6 .5 cm in d iam ete r. F iv e con tiguous ax ia l sec tions w ereob ta ine d du ring a 7 .0 -mm da ta a cqu is it io n pe riod . E ach s lice w a s 4 .2mm th ic k a nd spa tia l reso lu tio n w as 1 .0 x 1 .0 m m. T A (pu lse ) in te rva lw as e ithe r 500 o r 1 000 m sec; TE (echo de la y) w as e ithe r 28 o r 56m sec a fte r the 90# {176 }ad io frequency (AF ) pu lse . The sam e im ag ingfa c to rs w ere used th roughou t the in v itro and ra t im ag ing p ro to co ls .Fo r each o f the fiv e ax ia l sec tions , fou r sp in -e cho im ages w e reob ta ine d de s ig na ted a s S E 500 /2 8 , SE 500 /56 , S E i 0 00 /28 , a nd SE1 000 /56 (the num be rs ind ica ting T RIT E).

Me a n in ten s ity va lue s , in a rb itra ry un its o f in te n s ity re la te d to th evo ltage o f the rece ived AF pu lse , w e re de te rm ined fo r ope ra to r-de fine d reg io n s o f in te re s t. E a ch reg io n o f in te res t co n ta in e d a t le as t50 p ixe ls . P ixe l-to -p ixe l s ta nd a rd de v ia tion in ea ch reg io n o f in te res twas a lso ca lcu la ted . The rece ive r ga in se ttin g and R F ou tpu t w e reno t a lte re d be tw een p re - a n d po s tco n tra s t im ages .

Im ag ing o f G ado lin ium -D TPA S olu tio ns in v itroG ado lin ium -D TP A (G d -DTP A ) as a m eg lum in e sa lt w a s p rep a red

as p rev ious ly descr ibed [4 ] and the 0 .5 m o l/L s to c k so lu tion wasd ilu te d w ith d is t ille d wa te r fo r in v itro im ag in g . Se rie s o f 7 .0 -m I te s ttu bes fille d w ith d is til le d w ate r o r gado lin ium -D TP A in concen tra tionso f 0 .01 , 0 .1 , 0 .3 , 0 .7 5 , 1 .0 , 1 .5 , 2 .0 , 5 .0 , a nd 20 .00 m o l/L w ereg rouped to ge the r fo r NM A im ag ing .

U ro gra ph ic Im ag in gNMR sp in -e cho -in te ns ity im age s w ere ob ta ine d in a se rie s o f fiv e

n o rm a l S p ra gue -D aw le y ra ts w e ig h ing 300 -40 0 g . G d -D TPA w aste s ted a s an in tra ve nous con tra s t-e nh anc ing agen t b y in jec tion in tota il ve in s o f ra ts a ne s the tize d w ith pe n to b a rb ita l (5 0 m g /kg in trap e ri-to nea l). SE im ages through the le ve l o f the k idneys w e re obta inedbe fo re and a t 5 , 1 2 , 3 0 , 6 0 , a n d 90 mm afte r G d -D TP A in jec tio n . T h edoses o f G d-D TPA ranged f rom 0 .01 to 1 .0 m mo l/kg . In tens ity reg ion -o f-in te re s t m easu rem en ts pe rm itted the assessm en t o f con tra s t en -hancem en t w ith in the re na l p a ren ch ym a and w ith in th e u rine .

E xpe rim enta lAbscess Im ag ingS te r ile in flam ma to ry le s ions (abscesses) w ere induced in th e

su b cu ta neous tis sue s o f th ree Sp rag ue -D aw ley ra ts a t th e le ve l o fth e k idn ey s by in jec ting 0 .4 m l o f ca rra geenan (0 .1 % w t/v o l) by am od ific a tio n o f the m eth od o f W in te r e t a l. [9 ]. Loca l reac tion to th ism ucopo lysaccha ride w as a llowed to deve lop ove r 4 h r. Then ra tsw e re im aged by NM R be fo re and up to 120 mm a fte r in tra venousin jec tio n o f 0 .1 o r 1 .0 m mo l/kg G d-DTPA . Ca rrageenan prev ious lyha s been show n to p roduce an edem atous pa tho log ic le s ion w ith inso ft tissues , reach ing a peak e ffe c t in 3 -5 hr [9 ].

R adia tion C ere britis Im ag ingA sm all fo cus o f rad ia tion -induced cereb r itis w as induced in a 7 kg

beag le by su rg ica l im p lan ta tion o f a 12 51 se ed d ire c tly in to the rig h tce reb ra l co rte x fo r a 48 -h r pe r iod [1 0 ]. T he ca lcu la ted rad ia tion doseto b ra in tissu e 1 cm from th e cen te r o f the se ed w as 1 500 rad (15G y). S even days a fte r ex tra c tion o f the rad ioac tive seed , the dog ,anes the tized aga in by in tra venous pen toba rb ita l, w as im aged us inga 0 .35 T supe rconduc ting NM A sys tem p rev ious ly descr ibed [1 1 ].

F ig . 1 .-S E 500 /2 8 NM R im age s o f a que ou s so lu tion s o f G d -DTPA . H ig he stin te ns ity w a s obse rved a t co n cen tra tion o f 1 .5 m mo l/L . N ot v is ib le is 2 0 m mo l/L s am ple . w h ic h ga ve no de te c tab le s ign a l du e to ve ry sh o r t T 2 relaxationt im e , le ss tha n 2 8 m sec .

F rom 500 and 1 500 m se c TA sp in -e ch o im age s , w e ca lcu la ted T iand T2 im ages o f the dog bra in [1 2 ]. The NM A im ag ing sequencesw e re pe rfo rm ed be fo re and up to 40 mm a fter adm in is tra tion o f 0 .5mm o l/kg G d -D TP A . T he in je c tio n w as m ade s low ly o ve r 60 se c . F ou rda ta acqu is itio ns a t 500 m sec TA w e re begun a t 5 , 1 0 , 20 , and 25mm afte r in je c tio n . A da ta acqu is ition a t 1 5 00 m sec TA w as begun32 m m a fte r in je c tion . A n ex te rna l re fe rence so lu tion , iron dex tran ,w as p la ced in the im ag ing fie ld to se rve as a s tanda rd fo r cons is tencyo f p re - a nd pos tc on tras t in te ns ity an d T i an d T2 va lu es .

T he p at ho lo gy induced by the 1251 seed in th is m ode l ha s beendescr ibed [1 0 ] and w as recon firm ed in th is a n im a l. B rie fly , a n on in -flam m a to ry a re a o f n ec ros is w as seen w ith in th e w h ite m a tte r w ithlo ss o f nuc le i and w ith axona l sw e llin g . A d ja cen t vesse ls show edp ro te in -rich flu id in th e p e r iva scu la r a n d in te rs titia l spa ce s .

Resu l t sIm ag ing o f G d-D TPA Solu tions in v itro

The 1 .5 mm o l concen tra tion o f G d -D TP A p roduced theh ighes t NM R in tens ity s igna l (1 2 ,1 23 un its 4 63 ) co mp are dw ith the base line in tens ity o f d is tille d wa te r (2 i 72 325 ) (fig .1 ). In tens ity w as a lso enhanced fo r the 0 .O i m m o l so lu tion(2428 367 ) and the 0 .1 mm o l so lu tion (5335 384). T he20 .0 mm o l so lu tion o f G d -DTPA had no obse rvab le s igna l andappea red b la c k on SE im ages. T h is obse rva tion is com pa tib lew ith a ve ry sho rt T2 re la xa tion tim e . A s im ila r dec rease insp in -ech o in ten s ity h as been obse rved w ith o the r pa ram ag -ne tic agen ts , fe rric ions and n itro x ide free rad ica ls , in h ighconcen tra tions [2 , i 3 ].

R ena l Im ag ingIn the se r ie s o f no rm a l ra ts , the nonenhanced k idneys

appea red as in te rm ed ia te - in tens ity s tru c tu res ou tlin ed byh igh - in tens ity pe rineph ric fa t. T he cen tra l co lle c ting s tru c tu res


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TABLE 1 : NMR C ha rac ter iz a tio n o f in -v ivo Ra t R ena lCom pa rtm ents be fo re and a fte r G d-D TPA A dm in is tra tion

D ose o f G d-D TP A(mmo l / k g ) :Rena l Compar tmen t

S E 5 00 /2 8 In te ns ity SDBe fo re A fte rC on tra s t C on tra s t

T im e o fIntens ityMeasu r emen t

(mm )

AJR : 1 42 , M arch 198 4 Gd-D TPA NMR IN AN IM A LS 62 7

F ig . 2 .-S E 500 /2 8 NM R im age o f n o rm al ra t ab dom en and re tro pe r ito neum .Low in ten s ity o f no nenhan ced u rin e in ren a l pe lv is . V ascu la r s truc tu re s w ithrap id ly flow ing b loo d, su ch a s in fe rio r v en a ca va ( IV C), h av e e ven lo we r intens ityth an u rin e.

w e re seen to con ta in low -in tens ity u r ine (fig . 2 ). T hese obser-va tio n s ag re e w ith th o se p re v iou s ly re po rted [3 , 1 4] (tab le i) .

A t 5 mm a fte r adm in is tra tion o f G d -D TPA in a dose o f 0 .im m o l/kg (the firs t im age ), the re was an in crease in rena lpa renchym a l SE 500 /28 in tens ity tha t reached a m ax im um o f3893 562 a fte r i 0 mm . B y 90 mm , the con tra s t agent w ass till e v iden t w ith in the k idney and rena l in tens ity w as 3517 51 7 . A ccom pany ing the in crease in rena l pa renchym a l in ten -s ity , the u rine w ith in the rena l co llec ting s tru c tu res becam em uch h ighe r in in tens ity , appea ring w h ite (fig . 3 ).

A low est e ffe c tive u rog raph ic dose o f G d -DTPA was no tde te rm ined from th is se rie s o f an im a ls because the low estte s ted dose (0 .01 mm o l/kg ) p roduced m a rked con tra s t en -hancem en t (fig . 4 ) w ith in the ur ine . T he pa renchym a d id no tenhance s ign ifican tly a t th is dose (< i SD ). C onve rse ly , a t theh ighes t te s ted dose (1 . 0 mm o l/kg ), the re w as ev idence o fp rom p t rena l e xc re tion and d iu re tic e ffe c t; the rena l ca lice sbecam e m a rked ly d is tended (fig . 5 ). H ow eve r, w ith th is h ighe rdose , the u r ine in tens ity dec reased to low e r than base linein tens ity a t 5 mm . Th is obse rva tion , co rre spond ing to the in -v itro obse rva tions o f concen tra tions app rox im a ting 20 mm o l/L , ind ic a tes m a rked sho rten ing o f T 2 re la xa tion tim es. S uchm a rked T2 sho rten ing is p red ic tab le from the spec trom e tncresu lts no ted fo r h igh concen tra tions o f G d -D TPA [4 ]. T hesam e ra t, by 85 mm a fte r adm in is tra tion , p resum ab ly w henG d -DTPA w as m o re d ilu te w ith in the u rine , had in creased SEin tens ity in the rena l pe lv is and pa renchym a (tab le 1 ).

E xperim enta l In flamm ation Im agingThe NMR im ages o f fla nk in flamm a to ry le s ions induced by

ca rrageenan w e re s trong ly enhanced a fte r in tra venous ad -m in is tra tion o f 0 .1 mm o l/kg G d -D TP A (fig . 6 ). T he 5 -mm im agerevea led a rim pa tte rn o f enhancem en t tha t fi lle d in com p le te lyby 35 mm . Th is change suggests a g radua l a ccum u la tion o f

1 .0 :Pa renchyma . . . 3509 39 6 2355 47 2

4089 38 4 585Ur ine 2703 297 1 1 97 41 6

38198865

850 .1 : Pa renchyma . .

Ur ine . 2901 41 22264 49 0 3893 56 2441 4 53 3 10100 .05 : Pa renchyma . .Ur ine

. 3261 89 62902 31 4

3783 52 74670 57 3

55

0 .01 : Pa renchyma . .Ur ine

. 3890 93 82943 391

3934 69 04281 48 4 605

Gd-DTPA w ith in the edem a tous in flamm a to ry le s ion ; th is e f-fe c t m ay be due to the g radua l d iffu s ion o f the pa ram agne ticcom p lex from the p la sm a in to the expanded in te rs titia l space .N o rm al so ft tissues in the con tra la te ra l fla nk and the ip s ila te ra lm usc le s d id no t change s ign ifican tly in in tens ity . The h ighe rdose (1 .0 mm o l/kg ) o f G d -D TPA s im ila r ly p roduced a m a rkedin c rease in SE in tens ity w ith in ca rrageenan -induced le s ionsfo r up to i 20 mm a fte r in je c tion .

R ad ia tion -Induc ed C ereb r itisThe foca l a rea o f rad ia tion dam age in the righ t ce reb ra l

hem isphe re o f a dog induced by a 1251 seed w as ba re lype rcep tib le as a low -in tens ity (3867 31 6 , SE 500 /28 ) zoneon the nonenhanced NM R sp in -echo im ages . A la rge so ft-tissue sw e llin g ove r the ca lva r ia a t the s ite o f c ran io tom y w aslow e r in in tens ity than ce reb ra l tis sues (fig . 7 ).

O n a ll SE im ages a t 5 -32 mm a fte r in tra venous in je c tion o f0 .5 mmo l/kg G d -D TPA , there w as an obv ious in tens ity in -c rease a t the s ite o f rad ia tion dam age . T he accum u la tion o fcon tras t agent can be assum ed to resu lt from foca l d is rup tiono f the b lood -b ra in ba rrie r. T he m ax im um SE 500 /28 in tens ityin c rease (5590 628 ) w as obse rved a t 25 mm . The ex te rna lre fe rence s tanda rd , iron dex tran , gave in te rna lly cons is ten tSE 500 /28 in tens ity va lues (m ean 12 ,495 35 ) fo r the fiveacqu is itio ns a t 500 m sec TA .

S im ila r to the ca rrageenan -induced flank abscesses , thesu rg ica l s ca lp le s ion showed a rim pa tte rn o f enhancem en ta fte r G d-D TP A.

T i im ages , ca lcu la ted from SE 500 /28 and SE i 500 /28da ta , dem onstra ted tha t the r igh t ce rebra l les ion be fo re con -tra s t had a re la tive ly long T i va lue (747 i 0 7 m sec) ascom pa red w ith the con tra la te ra l no rm a l b ra in (650 11 2m sec) (fig . 8 ). A co rre spond ing T i im age 34 mm a fte r G d -DTPA adm in is tra tio n (fig . 8 ) show ed sho rten ing o f T i to 633 i 3 2 m sec in the co re o f the le s ion , sugges ting accum u la tiono f the pa ram agne tic con tra s t agen t. Y e t, ad ja cen t to the zoneo f T i sho rten ing , a r im o f pe rs is ten tly long T i tissue (729


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R esu lts ind ica te tha t G d -D TPA com p lex , adm in is te red in -tra venous ly to an im a ls in expe rim en ts , a c cum u la te s in u r ineand ce rta in d iseased tissues to enhance in tens ity and in -c rease con tra s t on sp in -echo NM R im ages. B ecause o f therap id u r ina ry c lea rance o f G d -D TPA , m o re than 85% o f the

62 8 BRASCH ET AL. A JR :142 , M arch 1984

in je c ted dose appea ring in the u r ine w ith in 3 h r [4 ], the s ta tu s

95 m sec) w as obse rved . T h is pe riphera l z one o f tissue w ith D is cuss ionlong T i is sugges tive o f an edem a tous zone w ithou t s ign ifi-can t a ccum u la tion o f pa ram agne tic con tra s t agen t. The T itim e o f the no rm a l le ft ce reb ra l hem isphe re rem a ined essen -tia lly u nchanged 34 mm a fte r G d -DTP A adm in is tra tio n (625 i 0 7 m sec). The ca lcu la ted T i tim e o f ex terna l s tanda rdso lu tion was nea r cons tan t, le ss than 0 .5% d iffe rence be -tw een the tw o ca lcu la tions .

F ig . 3 .-S E 500 /2 8 NM R im age s o f on e ra ta r ranged in te m po ra l o rd er (le ft to righ t, to p tobo ttom ) b e fo re in tra ven ou s a dm in is tra tio n o f 0 .1m mo l/kg G d-D TP A an d 5 . 1 0 , 30 . 60 , and 9 0 m ma fte r a dm in is tr atio n. In cre as ed in te ns ity o f ren a lpa r enchyma an d u rin e a fte r G d-D TP A ad min is tra -tio n (s ee tab le 1) .

Fig . 4 . -SE 1 000 /28 NM R im ages o f ra t b e fo re(A ) a nd 5 m m afte r (B ) in tra ve no us a dm in is tra tio no f G d -DTPA (0 .01 mm ol/kg ). H igh s ign a l in te ns ityin k idney s a nd u ri ne a ft er c on tr as t.

F ig . 5 .-S E 100 0 /2 8 NM R im ages o f ra t k idn ey sbe fo re (A ) an d 5 m m afte r (B ) adm in is tra t ion o f 1m m ol/k g G d-D TP A. U rin e in d is te nde d re na l pe lv esa fte r in je ctio n is v ery lo w in in te ns ity , a ttr ib uta ble tom arked sh o r ten ing o f T2 w ith h igh do se o f co n tras tagen t. R ena l p a ren ch ym a is a ls o lo we r in in te ns ity(s ee ta b le 1 ).


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F ig . 6 .-SE 500 /28 NM R im ages o f ra t w ith ch em ica lly -ind uced rig h t fla nk no us in je c t ion o f 0 .1 mm o l/kg G d-DTPA . M arked in te ns ity in cre ase w ith ina bs ce ss . A , B efo re c on tra st a dm in is tra tio n. S oft-t is su e th ic ke nin g a nd re la tive ly a bs ce ss , p re dom in a te ly in nm pa tte rn . C , A t 3 5 m m . G d -D TPA has re ach edh ig h s ig na l in te ns ity c om pa red w ith con tra la te ra l flan k . B , 5 m m afte r in tra ve - co re o f ab sces s , p ro du c in g m ore e nh ancem en t.

F ig . 7 .-P recon tra s t SE 500 /28 (A ) a nd S E 1500 /28 (B ) NMR im age s o fdo g w ith f o ca l r a di a ti o n- in d u ce d ce re b ritis d em on stra te d as fa in tly lower-in tens i ty reg ion in A . E de ma to us su rg ica l w oun d in so f t t issues ove r ly ing brainles ion . C , S E 5 00 /2 8 im age 25 m m afte r 0 .5 m mo l/kg G d-D TP A g ive n in tra ve -no us ly . D , SE 1 500 /2 8 im age 7 mm afte r C . M arke d p os tc on tras t s ig na l-in tens ity en han cem en t a t s ite o f ra d ia tio n - ind uce d ce re b r itis an d in s ca lp w o u nd .

AJR :14 2 , M arch 19 84 Gd-D TPA NMR IN AN IM ALS 629

o f rena l func tiona l in tegr ity shou ld be assessab le by G d -DTPA-e nhan ced NMR im ag ing . A dd itio na l s tud ie s in an im a lsw ith rena l func tiona l abno rm alitie s need to be pe rfo rm ed toassess m ore com ple te ly the sens itiv ity o f G d -D TPA -enhancedN M R u ro gra ph y.

T he ab ility to con tra s t-enhance s te r ile in flam ma to ry le s ions ,induced e ithe r by a chem ica l irr ita n t o r by su rge ry , is ano the rc lin ic a lly im po rtan t p rope rty o f the G d -D TPA com p lex . F romou r obse rva tions it seem s like ly tha t G d -D TPA d is tr ib u te sp rim a rily in the in tra vascu lar, e x tra ce llu la r space and qu ick lypasses in to the ex tra vascu la r, in te rs titia l s pace . A s im ila rpa tte rn o f d is trib u tion is we ll e s tab lished fo r d ia trizoa te , acomm on ly used rad iog raph ic con tra s t agen t hav ing a m o lec-u la r w e igh t o f abou t 600 . B y com pa ris on, the m o lecu la rw eigh t o f G d -D TPA com p le x is 590 . T he com pos itio n o fin te rs titia l flu id w ith in tissues is ve ry s im ila r to the p la sm aw ith in the vascu lar com pa rtm en t. B o th flu id s have ra the r longT i re la xa tion tim es and y ie ld low s igna l in tens itie s on NM Rim ages com pa red w ith the s igna l from high ly ce llu la r tis sues .W e postu la te tha t a fte r in tra venous in je c tion , G d -D TPA in thep la sm a d iffu ses in to the ex tra vascu la r, in te rs titia l s pace andthus w ill consp icuous ly enhance tissues w ith a h igh p ropo rtiono f in te rs titia l flu id (e .g ., edem a tous tissue ). C onve rse ly , tis -sues w ith a re la tive ly la rge ce llu la r pa rt and sm a ll in te rs titia lpa rt w ou ld be expec ted to con ta in a re la tive ly sm a lle r con -cen tra tion o f G d -D TP A and thus to dem ons tra te little o r noenhancem en t on NM R im ages .

The ab ility o f G d -D TPA to con tra s t-enhance se le c tive ly apa tho log ic fo cus w ith in the b ra in is pe rhaps the m os t c lin ica llys ign ifican t o f the po ten tia l app lica tions dem onstra ted . Theresu lts o f ou r s tudy , lim ited to one an im a l w ith fo ca l rad ia tionce reb r itis , sugges t tha t G d -D TPA con tra s t enhancem en t m aya id in the d iffe ren tia tio n o f necro tic tissue from su rround ingedem a . B e fo re c lin ic a l tr ia ls , a va rie ty o f cen tra l-ne rvous -sy s tem -d isease an im a l m ode ls shou ld be tes ted w ith G d -D TPA NMR im ag ing .The d iagnos tica lly e ffe c tiv e in tra venous doses o f G d -DTPAused in th is s tudy (0 .01 -0 .5 mm o l/kg ) a re fa r le s s than theLD 50 dose in ra ts (1 0 mmo l/kg ) [4 ]. In fu tu re im ag ing te s ts ,u s in g sm alle r Gd-D TPA doses , the ra tio be tw een LD 50 andlow est d iagnos tica lly u se fu l doses m ay even be g rea te r thanthe 1 000 :1 ra tio sugges ted he re .

In summ ary , te s ting o f G d -D TPA as an NM R con tra s t-enhanc ing agen t ind ic a te s tha t th is pa ram agne tic com p lexcan be used e ffe c tiv e ly in an im a ls fo r a va rie ty o f d iagnos tic


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63 0 BRASCH ET AL . AJR :1 42 , March 1984

F ig . 8 .-T i im a ge s o f sam e do g sh ow n in f ig . 7ca lcu la ted from S E intensity d a ta . L on g T i va lue sare d ep ic te d as w hite ; sh o rt T i va lues a re re la tive lyb lack o n gray-sca le ass ignm en ts . A , B e fo re co n -tras t . Long T i va lue o f ce reb ra l a nd so ft-tis su ele sio ns . B , 3 4 m m a fte r a dm in is tra tio n o f 0 .5 m mo l/kg G d -DTPA . P ostco n tra s t T i sh o rte n ing in cen te ro f ce reb ra l les io n (b loo d-b ra in ba rrie r [ BB B I d ef ec t)is sh ow n as b lac k a rea . S urrou nd in g zo ne o f w hitei nd ic a te s r eg io n o f pe rs is te n tly lo ng T i , presumab lyzone o f e dem a w ith ou t s ig n ifican t ac cum u la t ion o fpa r amagne t ic agen t .

pu rposes . G d-D TP A is s trong ly pa ram agne tic , is rap id ly ex-c re ted , can be p repa red from read ily ava ilab le m a te ria ls , isno t m e ta bo lize d in the bod y , a nd w as w e ll to le ra ted in o u rsm a ll g roup o f an im a ls . G d -D TPA , used c lin ica lly in pa tien tsa fte r app rop ria te tr ia ls , m ay ex tend the d iagnos tic u tility o fN MR im ag ing exam ina tions .

A C KNOWLEDGMENTSW e than k John R . F ike and C hr is to ph e r E . C ann fo r as s is ta n ce in

pre pa rin g th e m ode l o f ce reb ra l ra d ia tion ne cros is , a nd F ran k G orh amfo r h e lp in m anu sc rip t p rep a ra tio n .

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1983 animal studies using gd-dtpa weinman

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