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CLINICAL SCIENCES
Reversal of Brain Metabolic Abnormalities
Following Treatment of AIDS Dementia
Complex with 3'-azido-2',3'-
Dideoxythymidine (AZT, Zidovudine):
A PET-FDG Study
ArturoBrunetti, GaryBerg,Giovanni Di Chiro,RobertM. Cohen,
RobertYarchoan,PhilipA. Pizzo,SamuelBroder,Janie Eddy,MichaelJ. Fulham,
RonaldD. Finn, and StevenM. Larsont
Neuroimaging Section, NINCDS; Nuclear Medicine Department and Clinical Brain Imaging Section, NIMH; Division ofCancer Treatment and Pediatric Branch NCI; and National Institutes ofHealth, Bethesda, Maryland
Brain glucose metabolism was evaluated in four patients with acquired immunodeficiency syndrome (AIDS) dementia complex using [18Flfluorodeoxyglucose(FDG) and positron emissiontomography(PET) scansat the beginningof therapywith 3'-azido-2',3'- dideoxythymidine (AZT, zidovudine), and later in the course of therapy. In two patients, baseline,largefocalcorticalabnormalitiesof glucoseutilizationwere reverseddunngthe
courseof therapy.Intheothertwopatients,theinitialPETstudydidnotrevealpronounced
focal alterations, while the post-treatment scans showed markedly increased cortical glucose
metabolism.Theimprovedcorticalglucoseutilizationwasaccompaniedinallpatientsby
immunologicand neurologicimprovement.PET-FDG studiescan detect corticalmetabolic abnormalitiesassociatedwith AIDS dementiacomplex,and may be usedto monitorthe metabolic improvement in response to AZT treatment.
J Nuci Med 30: 581—590, 1989
evere cognitive, behavioral, and motor abnormali
ties occur frequently in patients with acquired immu
nodeficiency syndrome (AIDS) in the absence of op
portunistic infections or tumors of brain. This condi
tion, which is associated with pathologic abnormalities
primarily involving the white matter, is known as AIDS
dementia complex (1—4).It usually appears late in the
course of AIDS and, characteristically, once symptoms
havebeenestablished,thereis rapidprogressionof the
disease in the absence of treatment (1). However, cog
nitive dysfunction attributableto human immunodefi
ciency virus-l (HIV-l) can occur early in the course of
the disease and can be rather subtle. In particular,
Received Aug. 3, 1988; revision accepted Jan. 18, 1989. For reprints contact: Giovanni Di Chiro, MD, Neuroimaging Section, NINCDS, NIH, Bldg. 10, Rm. 1C451, Bethesda, MD 20892.
. Present address: Medicina Nucleare-Istituto di Scienze Ra diologiche, 2nd Medical School, Naples, Italy. + Presentaddress:Nuclear Medicine,Memorial Sloan-Ketter ing Cancer Center, New York, NY.
symptoms may occur earlierin children (2,3) and some
impairment appearsto affect nearly all patients (3). 3'-
azido-2',3'-dideoxythymidine (AZT, zidovudine) has
been reported to be successful in the treatment of AIDS
and AIDS dementia complex (5—8).In a preliminary
report (7) we noted that one patient with AIDS demen
tia complex had a normalization of the pattern of
cerebral glucose utilization upon imaging with positron
emission tomography (PET) and fluorine-l8 fluoro
deoxyglucose ([18f@]p'@f@)In the present study, we re
port the PET-FDG studies of this and three additional
patients with AIDS dementia complex at the beginning
andin the courseof AZTtreatment.
MATERIALS AND METHODS
Patients
FourpatientswithAIDSdementiacomplexwerestudied
(three male homosexuals,ages32, 32, and 35 yr, and an 11-
yr-old boy with hemophilia). The patients were all treated
Volume30 •Number5 •May1989 581
with AZT according to protocols of the National Cancer Institute. Informed consent for evaluation and PET studies were obtained from the patient or their guardians. In every
casea thoroughclinical,immunologic,and neurologicassess
ment was carried out prior to and during AZT therapy. A series of neuropsychologic tests was used to assess intellectual ability, memory, motor performance, attention, and onenta tion in the three adult patients. Intellectual ability, verbal
performance,and developmentwere evaluated in the 11-yr
old boy. The resultsof the psychometrictests have been
previously reported (6—8).
PETStudies
PET studies were performed 45 mm after i.v. administra
tionof 5 mCi(185 MBq)FDGin thethreeadultpatientsand
2.5 mCi (93 MBq) FOG in the pediatric patient. Timed arterial
blood samples were obtained from the radial artery in the
three adult patients. Timed venous blood samples were oh
tamed from a central venous catheter in the I 1-yr-oldboy.
During the interval between the administration of FDG and
the PET scan the patientswere kept at rest in a darkened
room, but eye patches and ear plugs were not used. PET
studieswereperformedwitha ScanditronixPC-1024multi
slice scanner (5 mm in plane resolution, 11-mm-slice thick ness, and 13-slice separation). The attenuation correction was
performed in two patients with transmissionscans, while in
the other two patientsit was calculatedfrom an elliptical
outlinewith an automatedroutine.Glucosemetabolicrates
(GMR)werecalculatedaccordingto the Sokoloffmodel(9),
usingthe simplifiedoperationalequationderivedby Brooks
Image Analysis All PET images were first visually analyzed, in search of
focal areas of relativelyincreasedor decreasedglucoseutili
zation. Quantitative image analysis ofcortical metabolism was performed on five standardly selected supratentorial planes
(I 1). Regionalglucosemetabolicrates of cerebralcortexwere
determinedwitha standardseriesof 61 ROIs(Fig. 1).Mean
corticalGMRswerecalculatedfromthe regionalmetabolic
rates.Regional“scores―weresubsequentlyobtainedbydivid
ing in each study the regional metabolic rates by the mean
corticalGMR.This normalizationprocedurewasperformed
in order to obtain a quantitative evaluation of regional meta
bolic patterns,not dependenton absolute metabolicrate
values.Regionalscoresin the AIDSpatientswerecompared
with average regional scores determined in the group of ten
normal volunteers (Table 1). Mean normal scores ±3 s.d.
wereusedas a cutofflevelfordefinitionof hyper-andhypo
metabolicregions.
RESULTS
Case Reports
Patient 1. A 32-yr-old homosexual male with human immunodeficiency virus-l (HIV-l) infection diagnosed
in February 1985, was referred to the National Institutes
of Health (NIH) in July 1986 after a period of progres
sive mental deterioration. The neurologic examination
showed weakness of the extremities, with wide-based
gait. Nerve conduction studies and EMG showed a pauern consistent with sensori-motor neuropathy. The
psychometric evaluation revealed abnormal memory,
visual-spatial perception, and motor performance with
globally impaired mental ability. A post-contrast com
puted tomography (CT) scan showed moderate, gener aliZed, ventricular and sulcal dilatation, and pen-yen
tnicular white matter hypodensity. The patient was di
agnosed as having AIDS dementia complex. He was
started on AZT (zidovudine), 250 mg every 4 hr per os.
The baselinePET-FDGstudy, performedduringthe
second week oftreatment, showed an abnormal pattern
of cortical glucose utilization, with relatively increased
frontal metabolism, and relatively decreased temporo
occipital metabolism (Table 2). The quantitative ROI
analysis revealed three hypermetabolic frontal regions
(A2, D3, D4), one hypermetabolic midline parietal
region (A8), two symmetric hypometabolic temporal
regions (D6, D7), and two hypometabolic occipital
regions (Cl4, D 12) (see Table 1).
Regional metabolic asymmetries were no longer seen
in the repeatPET-FOG study, 10 wk afterthe beginning
of treatment (Table 2). The quantitative analysis of
B (^) D (^) E
FIGURE
Regionsof interestusedto evaluatecorticalglucosemetabolismin five standardlyselectedplanes13 mmapart.Plane
E, the most caudal,is 4 cm abovethe infra-orbito-meatalplane.Rightsideof figurecorrespondsto patient'srightside
inthisandinthefollowingfigures.
582 Brunetti,Berg,DiChiroetal TheJournalofNuclearMedicine
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584 Brunetti,Berg,Di Chiroet al The Journalof NuclearMedicine
regional cortical glucose utilization revealed no abnor
ma! scores in the repeat PET-FDG study. Concomi
tantly, the patient's mental and neurologic conditions
improved dramatically. His memory, attention, and
movementcoordinationimproved.Hismusclestrength
and his gait also improved,and the patientresumed
walking long distances unassisted. A repeat CT scan
showed no significant change compared to pre-treat
ment.The patient'smentalconditionremainedstable
for the next 3 mo of treatment. The dose of AZT was
decreased in December 1986 because of severe throm
bocytopenia, and he died 1 mo later from Pneumocystis
carinii pneumonia. Autopsy showed minimal spongy
changes in the medulla oblongata.
Patient 2. A 32-yr-old homosexual male with HIV-l
infection diagnosed in February 1986 was referred to
the National Institutesof Health (NIH) in October
1986, after a 6-mo period of progressivemental deteri
oration, with memory loss associated with decreased
writing ability and difficulties in concentrating. The
neurologic examination showed decreased coordina
tion, slowing of alternate movements, and generalized
weakness.The psychometricassessmentrevealedab
normal visual-spatial perception, motor performance,
and intellectualability.Post-contrastCT scan showed
mild brain atrophy, while magnetic resonance imaging
(MRI) demonstrated two symmetric areas of increased
signal intensity in each centrum semiovale in the T
weighted images (Fig. 2). A diagnosis ofAIDS dementia
complex was made, and the patient was startedon
AZT, 250 mg every 4 hr per os. PET-FDG studies were
performedatthebeginningandafter6 wkof treatment.
The baseline PET-FDG study did not reveal marked
focal cortical abnormalities (Fig. 3; upper row). The
regional score analysis demonstrated one hypermeta
bolic frontalregion (B3) and one hypometabolic frontal
region(A2). The repeatPET study showeda 30.6%
increasein meancorticalGMRcomparedto the base
line study (Fig. 3, lower row; Table 2). No abnormal
scores were found in the repeat PET-FDG study. The
patient'scognitive function improved substantiallyafter
being startedon AZT treatment.Psychometrictest
scores were back to normal values and a neurologic
examination showed normal coordination and speed of
alternating movements after 2 mo of treatment. No
changes were observed in the repeatCT and MRI scans,
compared to pre-treatment. The patient's mental con
dition remained stable in the following 7 mo of treat
ment. However, he subsequently developed cryptococ
cal meningitis and expired.
Patient 3. A 35-yr-old homosexual male with HIV-l
infection diagnosed in May 1985, was referred to the
NIH in November 1986 after a progressive deteriora
tion of his mental ability. A post-contrast CT scan
showedmild brainatrophyand periventricularwhite
matter hypodensity, with no focal lesions (Fig. 4). The
psychometric evaluation confirmed the diagnosis of
AIDS dementia complex, and the patient was started
on AlT, 250 mgevery4 hr peros. The baselinePET
FDG study showed low cortical GMR (Table 2). The
regional score analysis revealed three hypometabolic
regions (two frontal A2 and A3, and one left temporal
D6). The repeat study after 2 mo of treatment demon
strated a 79.9% increase of the mean cortical GMR
(Fig.5, Table2), withcorrespondent,marked,clinical
improvement. Regions A2 and D6 were still hypomet
abolic in the post-treatment study, where also one hy permetabolic occipital region (Cl4) was found. During
the first 2 mo of treatment the patient's alertness,
memoryand motor performanceimproved.The pa
tient responded to AZT treatment in the next 15 mo.
However, he subsequently developed HIV-l associated
cardiomyopathy, and expired.
Patient 4. An 11-yr-old hemophiliac boy, with HIV
1 infection diagnosed in 1984, was referredto NIH in
February 1987. The neurologic examination showed a
wide-based ataxic gait, weakness of the left ilio-psoas
and quadriceps,withbilateralpyramidalSigns.A psy
chometric evaluation revealed that he had lost 28 IQ
points compared to school testing that had been done
before he acquired HIV-l disease. A postcontrast brain
CT scan showed moderate brain atrophy and periven tricular white matter hypodensity more marked around
the right frontalhorn. The pre-treatmentPET-FDG
study showed a markedly abnormal glucose utilization,
with rightfront-temporaland left cerebellarhypome
FIGURE
Patient 2. Pre-treatment Trweighted MR images (TA = 2,000 msec; TE =
80 msec)showing mildbrainatrophy,
and symmetric areas of increased
signalintensityin eachcentrumse
miovale (arrows). Postcontrast brain CT scans(not shown)demonstrated bilateral penventricular white matter hypodensity, but no focal lesion.
Volume30 •Number5 •May1989 585
14.SS
a.. si
7. ii
26-NOV-86 28-JAN-
3.Si
FIGURE
Patient 3. Pre-treatment (left) and post-treatment (right) PET-FDG images (plane D). Low glucose utilization was observedin the pre-treatmentscan.The post-treatmentstudyshoweda 79.9% increasein meancorticalGMR. (Table
metabolic). At the time of the repeat PET-FDG study,
the mental status had significantly improved, while
neurological signs persisted. Control brain CT scans
showed disappearanceofthe white matter hypodensity.
The patient's mental status improved continuously and
his IQ returned to his pre-iliness level at 9 mo of
continuous AlT infusion therapy.
DISCUSSION
The neurotropism of human immunodeficiency vi
rus-l (HIV-l) is a Critical factor in the clinical course
ofAIDS. HIV-l is transportedacrossthe braincapillary
barrier by infected macrophages (12) and can subse
quently be found in glial and, rarely, neuronal cells
(13-15). In fact, the nervous and the immune system
share several cell surface receptors including CD4+,
responsible for HIV-l binding to helper/inducer lym
phocytes (16,17). The pathogenetic mechanism of
AIDS related neurologic disorders have not yet been
elucidated (3,4,6). AZT (zidovudine) can effectively
inhibit HIV-l replication (18) and can penetrate into
CSF (19). In addition, AZT has been shown to effec
tively inhibit HIV-l replication in monocyte/macro
phages (20). These observations suggest that AZT may reduce HIV-l replication in the brain and provide a rationale for its use in the treatment of AIDS-related
neurologic and psychiatric abnormalities (5-8).
PET-FDG studies can detect brain metabolic abnor
malities in different forms of dementia (21—25).Brain
metabolicabnormalitieswerealsodemonstratedin pa
tients with AIDS dementia complex by Rottenberg
et al. (26). Early relative subcortical hypermetabolism
and progressive cortical and subcortical hypometabo
lism were found to be characteristicof this groupof
patients. Since AZT can reverse AIDS related neuro
logic and psychiatric abnormalities (5-8), we designed
a feasibilitytrial for the evaluationof possiblebrain
metabolicchanges in patients with AIDS dementia
complex in the course of AlT treatment.
In regardto the effect oftreatment two patternswere
observed in the four patients. In two cases (Patients 2
and 3) the baseline study revealed minor focal abnor
malities of cortical glucose utilization, followed by
marked increase (30.6% and 79.9%, respectively) in
mean cortical GMR in the repeat study. In the other
two patients (1 and 4), the baseline study revealed
marked regional abnormalities ofcortical glucose utili
zation. These focal abnormalities were no longer cvi
Volume3O•Number5•May1989 587
@ 7.
@ I
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4,
A
16.
@ I
8.
@ I
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B
FIGURE
Patient4. Pre-treatment(Fig.6A)andpost-treatment(Fig.6B) PET-FDGimagesat the levelof the cerebellum(left)and
the basal ganglia (right). A: Baseline PET study shows left cerebellar (arrow) and right front-temporal (arrowheads) hypometabolism.B: Repeat PET study shows a normal cortical metabolicpattern, with persistent left cerebellar hypometabolism.
588 Brunetti,Berg,DiChiroetal TheJournalof NuclearMedicine
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