functional brain spect: the emergence of a powerful clinical

it is completely extracted from the blood into the brainand that it remains fixed within the brain without redistribution. Ofcourse, only microspheres injected directly intothe carotid artery satisfy these requirements completely.Nevertheless, those radiotracers that are available for brainperfusion imaging follow rCBF closely enough to be dinically useful. Furthermore, most routine clinical applications of brain perfusion SPECT do not require quantitation of TCBF and rely on the generation of images whichreflect tracer uptake and retention only. Quantitation ofregional cerebral blood flow with these radiotracers requires arterial sampling and careful modeling to accountfor incomplete extraction, back flux from the brain andother deviations from the theoretical model (1). Despitethese constraints, intravenous injection of brain perfusionradiotracers results in regional brain activity which correlates well with independent measures of rCBF over a widerange of flows.

Iodine-l23-isopropyl iodoamphetamine (IMP, Spectamine) was the first brain perfusion tracer to be synthesized and remains the most ideal with respect to its kinetics(2,3). Iodine-123 is not an ideal@ radionuclide since it isnot generator-produced and emits high-energy photons.The distribution of IMP reflects rCBF over a wide rangeof flows but may underestimate flow when plasma pH islow, as in cerebral ischemia or acidosis (1). Its first-passextraction by the brain is high, and peak activity is reachedwithin 15 to 20 mm (4). Brain imaging must be accomplished quickly after injection since redistribution is fairlyrapid and significant changes can be observed after 60mm. Since [â€˜23I)IMPis prelabeled by the commercialsupplier, logistic problems occur and emergency studiesare difficult to schedule. With the standard injected doseof 3â€”6mCi, the photon flux is low and image quality isnot as good as that with the technetium-labeled ligands.This becomes a particular problem with high-resolutionimaging systems.

Technetium-99m brain perfusion agents benefit fromthe optimal physical characteristics of the radionuclide,including its 140 keV monoenergetic photon, 6-hr halflife and potential for on-site labeling. Of the 99mTc radiopharmaceuticals that have been synthesized, only 99mTc@HMPAO (hexamethylpropyleneamine oxime, Ceretec) iscurrently available in the United States. It is a highly

J NucIMed 1992;33:1888â€”1904

ingle-photon emission computed tomography(SPECT) techniques provide a powerful window into thefunction ofthe brain and promise to become an importantcomponent of the routine clinical evaluation of patientswith neurological and psychiatric diseases. While it initiallyappeared that brain SPECT would suffer from a numberof limitations relative to positron emission tomography(PET), recent improvements in instrumentation and radiopharmaceuticals as well as increasingly compelling clinicalevaluations suggest a primary role for SPECT in the diagnosis ofa number ofhighly prevalent neurological diseases.SPECT imaging, even with high-resolution systems, issubstantially less expensive than PET and is more widelyavailable. Furthermore, a number of novel approaches todiagnosis have been developed for SPECT exclusively. Theimplementation of this method into clinical practice hasbeen slow, however, and its appropriate utilization willrequire much closer collaboration between nuclear medicine physicians, neurologists, psychiatrists and neurosurgeons.

RADIOPHARMACEUTICALS

Functional brain imaging requires radiotracers thatcross the blood-brain barrier, distribute proportionally toregional cerebral blood flow and remain fixed in the brainfor a sufficiently long time to permit SPECT imaging.Alternatively, blood flow can be measured quantitativelyfrom the clearance of the inert gas â€˜33Xewith highlysensitive instrumentation that can image its distributionrepeatedly during its rapid clearance from the brain.

For radiotracers that have a very slow clearance fromthe brain, estimates of regional cerebral blood flow (rCBF)are based on the microsphere model, which assumes thatthe radiotracer is freely diffusible from the blood pool, that

ReCeived Apr. 15, 1992; revision accepted Jun. 4, 1992.For reprints contact: B. Leonard Holman, MD, c@h*man, Department of

Radiology,Brighamand women's Hospital,75 FrancisSt., Boston,MA02115.

1888 The Journal of Nuclear Medicineâ€¢Vol.33 â€¢No. 10 â€¢October 1992

Functional Brain SPECT: The Emergence of APowerful Clinical MethodB. Leonard Holman and Michael D. Devous, Sr.

Department ofRadiology, Harvard Medical School and Brigham and Women â€˜sHospital, Boston, Massachusetts andDepartment ofRadiology, University ofTexas Southwestern Medical Center, Dallas, Texas

by on April 6, 2018. For personal use only. jnm.snmjournals.org Downloaded from

http://jnm.snmjournals.org/

soluble macrocyclic amine with rapid brain uptake butonly moderate first-pass extraction, which results in underestimation of rCBF (5,6). When regional cerebral bloodflow is quantified, this underestimation can be correctedby accounting for the freely exchangeable component ofHMPAO. Of the brain perfusion agents, 99mTc@HMPAOis the closest to a microsphere with virtually no brainwashout. The tracer remains fixed in the brain followingconversion to a hydrophilic compound in the presence ofintercellular glutathione ( 7). Because blood clearance isslow, perfusion defects are not seen as sharply as with otherbrain perfusion tracers. Technetium-99m-HMPAO follows blood flow and, when flow and metabolism areuncoupled as they are in luxury perfusion, 99mTc@HMPAOmay be increased or normal, while [â€˜231]IMPmay indicatea profound metabolic defect (8). The radiopharmaceuticalis chemically unstable in vitro and must be injected immediately after preparation.

Technetium-99m-ECD (ethyl cysteinate dimer, Neurolite) is currently undergoing clinical testing (9,10). Like99mTc..HMPAO,it has moderate cerebral extraction andunderestimates rCBF. Brain uptake is rapid and clearancefrom the brain is very slow. Blood clearance is rapid,resulting in a higher brain-to-background activity ratiothan with HMPAO. Furthermore, 99mTc@ECDis stable invitro.

With the inert gas clearance technique, rCBF is estimated from the clearance of â€˜33Xefrom the brain followinginhalation of the gas (11,12). This methodology can becoupled with SPECT with specially designed instrumentation. Because of the rapid clearance of the tracer, multiple studies can be performed on the same day. Quantitative measures can be obtained without arterial sampling.Limitations of â€˜33XeSPECT include the low photon energyofthe tracer and its rapid clearance from the brain, whichlead to poor spatial resolution. Specialized instrumentation is required with very high sensitivity in order to obtainmultiple images during the clearance of the tracer fromthe brain. The inhalation technique is more technicallydifficult than the intravenous method using brain perfusion radiotracers.

INSTRUMENTATION

A wide variety of imaging systems capable of highresolution brain SPECT are now available commercially.They fall into two categories: noncamera-based and camera-based systems. Noncamera-based systems include rotating detector arrays, fixed detector systems and multidetector scanners. The rotating detector array group includes the Hitachi four-head system, and the moreprevalent Tomomatic two-, three- and five-slice machines(Medimatic, Inc). The Tomomatic's most characteristicattribute is that it is capable of â€˜33XeSPECT, because ithas high sensitivity and can do rapid dynamic imaging(12). The Tomomatic, by changing collimators, can alsoproduce images of relatively high resolution (9â€”10mm)

using 99mTcHMPAO or [â€˜231]IMP.Collimator exchange isnot difficult, permitting case-by-case selection betweenâ€˜33Xeand high-resolution scans. The Hitachi rotating detector array system is also capable of both â€˜33Xeand highresolution (8â€”10mm) static imaging (13).

The original fixed-detector research systems that usemultiple detectors were the SPRINT (14) and the HEADTOME (15). They were designed with fixed detectorsoriented in a ring geometry with an internally rotatingcollimator. The Shimadzu (HEADTOME) system, whichis commercially available, is capable of high sensitivityâ€˜33Xestudies and moderate spatial resolution (10â€”12mm)using 1231or 99mTc.

The original multidetector scanner was the unit developed by Stoddart and colleagues (16), also known as theHarvard multidetector scanner (1 7), and is commerciallyavailable as the Strichman unit. This is a slice-based tornograph, as are the Hitachi, Shimadzu and Tornomatic, butit is built with very thick crystals that operate much likepinhole cameras as they traverse through space to obtaintomographic data. Hill et al. have demonstrated that thisdevice can image not only 99mTcand 1231,but also â€˜8Fin asingle-photon (not PET) mode (18). It cannot performâ€˜33XeSPECT.

Gamma camera-based systems are more prevalent todaythan dedicated tomographs, primarily because they can doboth head and body SPECT. There are two forms: singjehead and multihead systems. Modern tomographs haveovercome many of the limitations of the original systems,such as poor head alignment, magnetic field aberrationsand inadequate uniformity and linearity for tomography.A few of the modern single-head systems have also beendesigned to circumvent shoulders so that minimal radiusscanning is possible. Most of these systems provide fairlyhigh-resolution images with static tracers. Unfortunately,they suffer from poor sensitivity and prolonged imagingtimes.

Researchersfrom the University of TexasSouthwesternMedical Center at Dallas, in collaboration with the nuclearengineering division of Technicare, developed the firstthree-head gamma camera SPECT system (19) to addressthe limited sensitivity of single-head systems. Their intentwas to provide a system capable of both body and headSPECT at high resolution with static tracers and withadequate sensitivity and rotation speed for dynamic tomography with â€˜33Xe.The first three-head system wasinstalled in Dallas in late 1987 under the sponsorship ofOhio Imaging, now a division of Picker. Additional threehead SPECT instruments have been produced by Trionixand Toshiba. Prototype three-head instruments from General Electric and Siemens are also under evaluation. Currently, there are approximately 150 such units installed,indicating increasing acceptance of this technology.

A variant of the gamma camera approach utilizes asingle annular sodium iodide crystal (20â€”22). The ASPECT system, which is now commercially available, uses

1889Functional Brain SPECT â€¢Holman and Devous



a fixed annulus with rotating collimators (22). It yieldshigh spatial resolution (5.5â€”6.5mm) with excellent sensitivity. Xenon-133 dynamic SPECT acquisition is currentlyunder development.

State-of-the-art SPECT systems can be expected to provide high-resolution (6â€”9mm) imaging of statically distributed brain radiopharmaceuticals with patient imagingtimes of 10â€”20mm. All of the currently available threehead, annular and fixed detector ring systems (Picker,Trionix and Toshiba) offer excellent spatial resolution:with appropriate collimators and 99mTc@HMPAO, 6 mmresolution in the cortex and about 7 mm at the center ofthe brain. With [â€˜231]IMP,the photon flux is reduced, thusrequiring careful image processing to achieve equivalentspatial resolution. Images of99mTc@HMPAOand [â€˜231]IMPfrom the same normal control subject obtained on a threeheaded tomograph are shown in (Fig. 1).

Systems should also be capable of sequential imageacquisition; it should be possible to acquire multiple shortstudies back to back and subsequently discard segmentsdegraded by patient motion. Software should support dynamic filtering, multiple angle (oblique) reconstructions,surface-variable attenuation correction and three-dimensional as well as conventional cross-sectional displays. Themerging ofanatomic information from CT and MRI withSPECT is also necessary for accurate diagnosis and localization (23) and should be a critical element ofthe softwarepackage. Three-head and annular systems in theory shouldbe capable of â€˜33XeSPECT. However, dynamic scanninghas not been accomplished with any camera-based system.There is work in progress demonstrating such feasibilityfor the Picker and Toshiba systems.

SPECT systems should have adequate energy resolutionand multiwindow capability in order to separate 99mTcand1231 radiotracers in the same patient (24,25). While typical

gamma-camera energy resolution (12%â€”15%FWHM) isinsufficient to separate 140 keY (@mTc)from 159 keV(1231) photopeaks, high-resolution multidetector SPECT

units have substantially improved energy resolution. Theimages shown in Figure 1 were obtained simultaneouslyusing dual-isotope imaging of @mTc@HMPAOand [1231]IMP.

CEREBROVASCULAR DISEASE

The measurement of rCBF in patients with cerebrovascular disease was the earliest application of SPECT of thebrain. Numerous reports in the last decade describe applications for SPECT rCBF imaging in stroke, transient ischemic attacks (TIA), subarachnoid hemorrhage (SAH),arteriovenous malformation (AVM) and other derangements ofcerebral hemodynamics. Several valuable reviewsare available (26â€”28).Many ofthese reports promote bothdiagnostic and prognostic roles for SPECT rCBF imagingof cerebrovascular disease, although criticisms have beenraised that current investigations do not directly addressthe questions of greatest importance to the referring physician (29,30).

SPECT is superior to anatomical imaging procedures indetecting cerebral ischemia during the first hours followingan ictus because rCBF alterations occur earlier and arebetter defined than structural changes. Knowledge of perfusion status has important clinical applications in thedifferential diagnosis and initial management of patients

FIGURE 1. High-resolutionSPECT images of @â€˜TcHMPAO (left) and [123I]IMP(right) in the same normal volunteer. Images were obtainedsimultaneously by dual-isotopeacquisitionof the two radiotracars injected sequentially. A128 x 128 acquisitionmatrixwas employed using a highresolution(7â€”8mm)fanbeamcollimatorand a three-headedSPECT system. Note similarimage resolution for both brainbloodflowtracers.

1890 The Journal of Nuclear Medicineâ€¢Vol.33 â€¢No. 10 â€¢October1992

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with cerebrovascular disease. In patients with TIA, SPECTmay provide the only objective documentation ofthe ictus.The detection of hemodynamic alterations is also important in patients with silent strokes and other asymptomaticlesions to facilitate patient subtyping and management.

StrokeSPECT is useful in the detection ofacute cerebral ische

mia. Regional CBF alterations occur instantly in patientswith stroke, while CT and MRI are typically normal duringthe first hours to days after the ictus (Fig. 2). For example,by 8 hr after infarction, only 20% of CT scans will bepositive (31,32), while at the same time approximately90% of SPECT rCBF scans will be abnormal (33,34). Thedifference in sensitivity between structural and functionalimaging modalities disappears within about 72 hr. Inaddition, the sensitivity of SPECT is significantly reducedfor lacunar infarctions.

Sensitivity for lesion detection is also affected by luxuryperfusion (35), wherein perfusion and metabolism becomedecoupled beginning approximately 5 days after the ictus,and continuing for as much as 20 days (Fig. 3). Althoughthis phenomenon is not well understood, it is well documented (8,12,26,27) and false-negative studies can resultduring this period. Thus, acute rCBF imaging may beeffective, but imaging during the subacute phase is insensitive, particularly with 99mTc@HMPAO(8).

Crossed-cerebellar diaschisis frequently accompaniescortical strokes because cortico-pontine-cerebellar linkagesnormally provide stimulation to the cerebellum contralateral to the indicated cortex. Reduced perfusion to thecontralateral cerebellum is a common secondary phenomenon following cerebral ischemia, which continues evenduring luxury perfusion (36,37).

SPECT rCBF imaging may also be useful in delineationof stroke subtypes. Since evolving therapeutic regimensare subtype-specific, it is increasingly important to providerapid, accurate classification of the acute episodes. Forexample, case selection for endarterectomy may dependon the identification of patients with ongoing low-flowstates even in the presence ofasymptomatic carotid disease

FIGURE 3. Mid-levelandinferiorlevel(containingcerebellum)SPECT brain blood flow images in a stroke subject demonstratea left hemispheric flow deficit on the day of the ictus that partiallyresolvesby 24 hr. Apparentresolutionof the deficitat Day 7representsluxuryperfUSiOnto an infarctedand metabolicallyabnormal zone. By Day 33, the flow disturbance retums to alevel similar to that seen initially. Note that crossed cerebellardiaschisisispresent and does not resolveduringluxuryperfusion.

(28,30). In acute infarctions, distinguishing between theappropriateness of anticoagulation or thrombolytic therapy may depend on the demonstration of the physiologicsignificance of an angiographically demonstrable lesion.The use ofcalcium channel blockers may only be effectiveprior to induced or spontaneous reperfusion.

The measurement of cerebrovascular reserve is particularly well suited to rCBF imaging. Two indices of reservecan be obtained. The rCBF-to-rCBV (flow/volume) ratiomay be related to the regional oxygen extraction ratio andprovides an indirect measure of perfusion pressure (38â€”40). Cerebrovascular reserve can also be measured following the vasodilatory response to C02, or acetazolamide, acarbonic anhydrase inhibitor and potent cerebral vasodilator (41â€”43). Measurements of cerebrovascular reserveare useful in assessing either the need for acute interventions following stroke or the risk status for secondarystrokes. A recently developed dual-isotope imaging technique (24) facilitates the measurement of cerebrovascularreserveby SPECT (25) (Fig. 4).

Several recent studies also suggest a prognostic role forSPECT in stroke. A direct relationship between rCBF andclinical outcome has both been supported (44â€”48) andrefuted (49-51). Improved correlation between rCBF andoutcome has been achieved with measurement of thevolume of the rCBF defect relative to the volume ofstructural defect (52) or of the volume of the flow lesionalone (28,53â€”55).One ofthese studies (55) showed a 92%predictive power of ICBF SPECT obtained within 6 hr ofthe ictus for poor neurologic outcome.

Distinctions between [â€˜231]IMPand 99mTc@HMPAOhave been reported. IMP may provide more contrast forareas of ischemia than HMPAO, particularly in the subacute phase (8,56). Reduced lesion contrast with HMPAO

FIGURE 2. Abnormalperfusionin the distributionof the rightmiddle cerebral artery in an acute stroke patient 6 hr after onsetof symptoms. A concurrent CT scan was normal. A repeat CTstudy was abnormal three days after ictus.


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may be a consequence of flow-dependent backdiffusion(57) andhigh initial bloodlevels(58). A comparisonofearly and delayed (4 hr postinjection) IMP uptake has beenproposed as an indicator of tissue viability (47), althoughthis is not well established (54).

Transient Ischemic AttacksDetermination of the cause of a TIA (thrombotic, em

bolic or hemodynamic) has substantial impact on patientmanagement. Structural imaging contributes little. Forexample, Crow and Guinto found that 82/100 TIA patients had normal CT scans; the 12 patients with abnormalscans showed only the nonspecific finding ofatrophy (59).SPECT rCBF imaging may clarify the mechanism of ischemia (60) and may identify patients at the highest riskfor subsequent infarction in the first week following TIA(61). The value of SPECT imaging in TIA patients maybe increased by assessing the status of vasodilatory reserveand the response to medical or surgical intervention. Suchassessments are important since as many as 60% of TIApatients will go on to have a completed stroke (62). Thesensitivity of rCBF imaging in TIA declines with time,from 60% in the first 24 hr (63) to less than 40% 1 wkafter the event (34). This sensitivity may be enhanced bothearly and late after the ischemic event by examination ofcerebrovascular reserve with acetazolamide (61,64).

Subarachnoid HemorrhageSubarachnoid hemorrhage accounts for approximately

one-halfofall intracranial hemorrhagic strokes. Post-hemorrhage neurologic deficits that appear within 2 wk aremost commonly a consequence of vasospasm (65). Consequent delayed cerebral ischemia and possible infarctionmake vasospasm an equally important factor with recurrent hemorrhage in the morbidity or mortality of subarachnoid hemorrhage. Management of subarachnoid hemorrhage patients requires the differentiation of vasospasmfrom edema, elevated intracranial pressure, hydrocephalusand electrolyte aberrations (66). Vasospasm is accompanied by decreased rCBF, decreased cerebral metabolism,increased neurologic deficit and increased cerebral bloodvolume (67,68). Davis et al. found a correlation betweenregional hypoperfusion evidenced by HMPAO SPECT andthe presence and severity of a delayed neurologic deficitin subarachnoid hemorrhage patients (69). While the presence of vasospasm can be documented by transcranialDoppler (70) or angiography, these studies only indirectlyrelate to the risk for cerebral infarction. Regional CBF orrCBF/rCBV imaging provide a more direct measure of thehemodynamic significance ofobserved vasospasm. By providing early evidence of cerebral ischemia, SPECT mayhelp to differentiate vasospasm from other causes of neurologic deterioration following subarachnoid hemorrhageand thus enhance delivery of therapeutic measures designed to reduce its effects.

Arteriovenous MalformationPatients with arteriovenous malformation are at risk for

three major complications: (1) intracerebral or intraventricular bleeding, which may occur at any time and maybe fatal [the incidence of spontaneous hemorrhage rangesfrom 35% to 60% (71)]; (2) seizures; and (3) intracerebralâ€œsteal,â€•in which relative ischemia is produced in parts ofthe brain either adjacent to or remote from the arteriovenous malformation due to high arterial-to-venous shuntingthrough the arteriovenous malformation (72). Xenon-l33SPECT studies have demonstrated a high incidence ofsteal (72-75). Documentation of steal has provided amotivation for staging of surgical resection and for presurgical treatment with arterial embolization (74, 75). Thearteriovenous malformation itself appears as a high-flowregion on â€˜33XeSPECT, but as an area of reduced traceruptake with IMP or HMPAO since the vascular malformation does not retain these tracers. Devous, Batjer andcolleagues found that the examination of cerebrovascularreserve with acetazolamide in arteriovenous malformationpatients was prognostic for postoperative outcome (76,77).

Future ProspectsEven though SPECT rCBF measures provide sensitive

early detection ofcerebrai ischemia, and may provide bothdiagnostic and prognostic information in stroke patients,no significant change in the frequency of referral fromneurologists for SPECT has been observed. Brass andRatner have identified several relevant factors (30). First,the complete implementation of rCBF SPECT imaging inthe evaluation ofpatients with cerebrovascular disease willrequire a far more thorough interdigitization ofthe nuclearmedicine physician and the neurologist in evaluating, improving and implementing this potentially valuable technique. Second, purely descriptive studies, often performedin isolation from a clear statement of relevant clinicalproblems, contribute little to understanding the role ofSPECT rCBF measurements in patient management orenhancing the referring physician's perception of the usefulness of this technique. Prospective studies should bedesigned to answer focused questions relating to issues ofclinical management. Finally, thorough evaluation ofâ€œbrainstress tests,â€•specifically the measurement of vasodilatory reserve, is important since current clinical orstructural imaging measures are limited in their ability todetermine risk status. An increased recognition of theimportance of hemodynamic measures relative to structural assessments (78) places new emphasis on the evolution of activation or intervention studies (42) which enhance risk assessment. The current role for rCBF SPECTimaging in cerebrovascular disease can only be recognizedand expanded through careful cooperative efforts betweenthe nuclear medicine and neurological communities.




Functional Brain SPECT â€¢Holman and Devous 1893

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FIGURE4. Three-dimensionalsurface-renderedimagesshowing a right frontopanetal resting rCBF deficit with expansionfollowing vasodilation with Diamox in a stroke patient. The difference in affected areas in the resting and vasodilated studiesrepresentstheareaof failedvasodilatoryreserve.

DEMENTIA

Alzheimer'sDiseaseApproximately halfofthe patients presenting with early

clinical symptoms of dementia cannot be accurately diagnosed by clinical criteria. Early diagnosis is importantbecause dementia-like symptoms may mask reversibleconditions, such as depression, or treatable diseases, suchas vascular dementia. Furthermore, early diagnosis of Alzheimer's disease can avoid the financial and emotionaldrain that often occurs if the time to final diagnosis isneedlessly delayed.

Brain perfusion SPECT is useful in the diagnostic evaluation of patients with memory and cognitive abnormalities (79). Initial clinical studies comparing patients withAlzheimer's disease and normal control subjects (80â€”87)or patients with multi-infarct dementia (88â€”91)found thatSPECT is highly accurate. In severely impaired patients,sensitivity is 95% or greater ( 79,83). The sensitivity ofSPECT in the classification of mildly impaired patients isalso high, with rates reported between 80% and 87% (79,86,92).

The predominant finding ofbilateral posterior temporaland parietal perfusion defects in these patients is highlypredictive of Alzheimer's disease (Fig. 5). In a prospectivestudy of over 100 patients with memory loss, bilateralposterior association cortex defects were detected with99mTcHMPAO SPECT in 65% of the patients with Alzheimer's disease (93). This pattern, with or without additional association cortex defects, has a predictive value ofover 80% for the diagnosis of Alzheimer's disease.

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FIGURE 5. Technetium-99m-HMPAOSPECTusingthe highresolutionASPECTsystem.Bilateraltemporoparietalperfusiondefects ina patient with Alzheimer's disease. Axial(A)and sagittal(B)planes.

While bilateral posterior cortical defects are highly predictive in Alzheimer's disease, this scintigraphic patternhas also been described in patients with vascular dementia(91), Parkinson's disease (94,95), mitochondrial encephalomyopathy (96), hypoglycemia (97) and carbon monoxide poisoning (97). The scintigraphic pattern of Parkinson's disease with dementia cannot be distinguished fromthat of Alzheimer's disease by visual assessment alone.While Parkinson's disease patients with dementia have avariety of scintigraphic patterns, the most common involves the temporoparietal cortex (94,95).

The reduced tracer uptake in the posterior associationcortex in patients with Alzheimer's disease is probably dueto multiple factors, including reduced rCBF, decreasedcortical thickness in the temporoparietal cortex (98) anda reduced number of neurons in the affected areas (99).Most of the reduced tracer activity is due to reducedregional blood flow, however, particularly in early disease(100). In any case, the combined effect of flow reductionand atrophy serve to increase the diagnostic sensitivity ofthe test, and atrophy corrections are probably not warranted for routine applications.

Patients with Alzheimer's disease can present with other



scintigraphic patterns, although they are less frequent thanbilateral posterior cortical defects (93). Unilateral temporoparietal defects are not predictive either for or againstAlzheimer's disease. With 99mTc@HMPAO,unilateral postenor defects are seen in 15%â€”20%of patients with Alzheimer's disease (93), significantly more than with [1231]IMP (80). Consequently, vascular dementia involving theposterior branches of the middle cerebral artery may resemble Alzheimer's disease when the latter presents as aunilateral pattern.

Some investigators recognize dementia of the frontaltype as an entity separate from Alzheimer's disease (92),with the former presenting with personality and behavioralchanges and with less severe memory deficits. These investigators find that the two dementias can be distinguished scintigraphically, with bilateral frontal or frontotemporal deficits characteristic of frontal lobe dementia.Frontal dementia is considered by many to be a subset ofAlzheimer's disease. In either case, bilateral frontal deficitsby themselves are not diagnostic and are seen in patientswith schizophrenia, depression, progressive supranuclearpalsy (usually with basal ganglia involvement) and Pick'sdisease as well as in Alzheimer's disease and/or frontallobe dementia.

The probability of Alzheimer's disease with normalperfusion or with perfusion defects outside the temporoparietal cortex is low. The predictive value of a normalscan depends on the clinical setting. When patients arewell screened before referral for SPECT, few of them willbe without central nervous system disease. In our experience, when patients are screened by a memory disorderclinic, the negative predictive value of a normal study isabout 80%. The predictive value will increase as morenormal patients are included in the population.

VascularDementiaVascular dementia is related to a number of distinct

underlying diseases (101). Binswanger's disease or subcortical atherosclerotic encephalopathy involves the microcirculation, presents as white matter disease and is attributedto atherosclerosis of penetrating cerebral arteries. Multiinfarct dementia involves the large vessels and results fromlarge cerebral infarcts. A third disease, a form of multiinfarct dementia but not usually involving large-vesselocclusion, results from multiple small, deep, subcorticallacunar and pericapsular infarctions. Mixed forms of thesethree vascular diseases often occur. Technetium-99m-HMPAO SPECT appears reasonably accurate for distinguishing vascular dementia from Alzheimer's disease whenbilateral temporoparietal defects are present (82,83). Thescintigraphic pattern of multi-infarct dementia is usuallydescribed as multiple asymmetrical perfusion defects, ofteninvolving the primary cortex and deep structures. Vasculardementias which involve the subcortical structure are associated with patchy or diffuse patterns of blood flowreduction.

AIDS Dementia ComplexThe early clinical signs of AIDS dementia complex

(ADC) or HIV encephalopathy are often subtle and maybe indistinguishable from depression, psychosis or focalneurologic disease. Since treatment such as zidovudine(AZT) can improve cognitive function in ADC, its earlydetection is important. Computed tomography (CT) andmagnetic resonance imaging (MRI) play a role in diagnosing focal neurologic disease, such as infection or tumor,but are nonspecific for ADC. Brain perfusion SPECT ishighly sensitive for the detection ofADC (102â€”104).Earlydisease is easily separated from normal subjects and nonHIV psychoses (105â€”106).The perfusion pattern is usuallydescribed as multifocal or patchy cortical and subcorticalhypoperfusion. With high-resolution SPECT, we found ahigh incidence of cortical defects in ADC, which are mostfrequent in the frontal, temporal and parietal lobes (107)(Fig. 6). Background activity is high, involving more thanhalfofthe patients in our series. Basal ganglia involvementis also frequent. A high number of patients have focalareas of increased activity as well. The perfusion patternimproves with ADC therapy (105). Brain perfusionSPECT should be applied cautiously in patients with suspected ADC because an identical brain perfusion patternis seen among chronic cocaine polydrug users (107). It isalso not clear whether the perfusion pattern is limited toADC or may be seen with nonspecific changes such aswhite matter pallor, astrocytic proliferation and mononuclear infiltration which are present in almost all AIDSpatients. It may not matter since SPECT imaging mayprove to be an indicator ofthe severity ofbrain dysfunctionand therefore may be quite useful in planning therapy andin evaluating its effectiveness.

EPILEPSYFunctional brain imaging with either SPECT or PET is

now a well-established technique to localize the epilepticfocus in patients with refractory complex partial seizures


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FIGURE6. Technetium-99m-HMPAOSPECT(axialplanes).Multiple small perfusion defects throughout the cerebral cortexin a patient with AIDSdementia complex.



(108). From 30% to 60% ofpatients with complex partialseizures ultimately become refractory to medical treatmentand may be referred for surgical removal of a discreteseizure focus. Since most complex partial seizures arisefrom temporal lobe foci (109), temporal lobectomy is theappropriate surgical therapy. Successful excision of welllocalized foci leads to elimination of seizures or significantly improved pharmacologic control in 80% of surgicalpatients (110). Traditionally, localization has been performed with scalp, cortical or depth EEG. However, scalpEEG may be misleading in the localization of the primarysite of seizure onset because it has inherently low spatialresolution and is fundamentally dependent upon primarilycortical surface effects. Surface electrocorticography is alsolimited by the area of brain sampled and its sensitivity toand localization of deep-lying generators. Depth EEG canmonitor deeper structures but samples only limited regionsofbrain. Both corticography and depth EEG are extremelyinvasive and present a surgical risk. Ward has reportedthat in the United States there are 50,000 patients withmedically refractory complex partial seizures possibly benefiting from temporal lobectomy (11 1). Of these, onlyapproximately 500 per year receive surgery, partially dueto the difficulty of adequate focus localization.

Interictal SPECT rCBF imaging is the most convenientand cost-effective technique for the localization of a temporal lobe focus in adult patients with medically refractorycomplex partial seizures. Studies to date would suggestthat, when an area of focal temporal lobe hypoperfusionis observed, the need for further studies is minimal (particularly if scalp EEG is concordant).

Partial Complex SeizuresInterictal Studies. Interictal PET studies of glucose me

tabolism have consistently demonstrated that approximately 70% of patients with complex partial seizures havediscrete foci of hypometabolism and that these sites mayoccur in more than one brain region in the same patient(112â€”121).There is a strong correlation between the areaof hypometabolism and the site of electrophysiologic abnormality determined by a combination of electrophysiologic data.

In rCBF studies employing â€˜33XeSPECT, only 50%demonstrate interictal hypoperfusion (122-124). Mostoften, hypoperfusion is found at the site of the EEGabnormality, but flow deficits are also seen in other remoteareas. No specific type of EEG abnormality is associatedwith reduced rCBF; equal flow reductions were seen in thepresence of focal spiking alone, focal spikes and slowingand focal slowing alone (125). The first high-resolutioninterictal scans with SPECT employed [â€˜231]IMPandHIPDM (126â€”129).More recently, interictal scans havebeen obtained with @mTc@HMPAOby a variety of investigators (130â€”134).Interictal SPECT findings with theiodinated amines and @mTc@HMPAOshow a frequency ofabnormal interictal hypoperfusion (70%â€”75%) similar toPET studies and excellent correlation with EEG localiza

TLE Interictal HypprIo@

FIGURE7. Interictalrighttemporallobehypoperfusionin apatient with temporal lobe epilepsy (TLE)on transverse andcoronalslicesusing[123l]IMP.The asymmetryof temporallobeperfusion is typical of the interictal state in such patients.

tion (Fig. 7). Rowe et al. (133) studied 32 patients withHMPAO, 30 of whom had temporal lobe localization byictal EEG; 18 of 30 patients had focal hypoperfusion atthe site ofthe EEG focus interictally. Devous et al. studied38patientswitheitherIMPorHMPAOinterictally,andin those patients with EEG-identified foci, approximately75%hadinterictalhypoperfusion(134).

Ictal Studies. HIPDM and IMP can be effectively usedfor ictal studies as long as careful EEG monitoring is usedto document seizure onset (Fig. 8). In the postictal phase,cerebral blood flow decouples from glucose metabolism;rCBF remains elevated (127,135), while glucose metabo

FIGURE8. Hyperperfusionoftherighttemporallobeisshownduring an ictus in a patient with temporal lobe epilepsy (TLE).This is the same patient shown in the interictal state in Figure 7.Note the reversal in asymmetry documenting seizure localizationto the right temporal lobe.

ThE Ictal Hyperperfusioii

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lism declines rapidly (118). In addition, secondary generalization may occur. Ictal studies with iodinated agentshave been more successfulin identifying seizurefoci thaninterictal studies (126,128,129,134). Unfortunately, trueictal studieswith HMPAO are nearly impossibleto obtainbecausethis compound is unstable in vitro, leading todelays between seizure onset and injection of 5â€”20mm.In the study by Rowe et a!., 22/30 patients with focal EEGfindings showed increased postictal HMPAO uptake at thesite of the EEG focus (133). These data suggest that earlypostictal studies (within 5 mm) may be as effective as trueictal injections.

In a recent review, the combination ofall EEG data waslocalizing in 71 % of the patients (108). By contrast, functional imaging (SPECT or PET) was localizing in 59% ofthe interictal studies and 65% of ictal studies. These datasuggest that ofthe patients with EEG-localized seizure foci,79% were equally well localized by functional brain imaging. It is interesting to note that the localizing power ofinterictal functional imaging is not substantially differentbetween SPECT and PET, nor is it significantly differentbetween IMP, HIPDM and HMPAO.

PrimaryGeneralizedSeizuresThere are few data concerning functional abnormalities

in generalized seizures (12,136â€”138). These results areconsistent with the failure of surface or depth EEG orstructural imaging modalities such as CT and MRI todefinea specificanatomicregionof seizureoriginin thesepatients (139). Leroy et al. did not detect quantitativeasymmetries in rCBF (137) and Theodore et al. found nosignificant differences in glucose metabolic rates (136).

FrontalLobe SeizuresIn recent years, there has been increased interest in

partial seizures originating from areas other than the temporal lobe (140). Frontal lobe seizures have been difficultto localize using standard EEG technique, and stereotacticdepth electrodes have not proven to be as beneficial forlocalizing the site of the seizure origin as in temporal lobeseizures. The results ofsurgical treatment of extratemporalpartial seizures has been disappointing in comparison tothe results of temporal lobe surgery. Functional imagingholds promise for localization of the site of extratemporalseizures, but limited data currently exist. It appears that60%â€”70%of subjects with proven extratemporal seizuresdemonstrate hypometabolism interictally (141). These hypometabolic areas appear widespread and are less localizedthan in temporal lobe seizures.

Structural,Clinicaland CognitiveCorrelationsPatients with partial and secondarily generalized sei

zures are much more likely to have structural abnormalities observable on CT or MRI than patients with primarygeneralized tonic-clonic seizures or absence attacks (142).It is not always true that abnormalities detected on structural imaging studies are correlated with the seizure focusdefined by clinical or EEG criteria or, for that matter, with

functional brain imaging. By far, the most common pathologic finding is mesial temporal sclerosis, which is thoughtto be the consequence of an older lesion now manifestedas a gliotic scar (143). A review ofSPECT and PET studiesdemonstratesa 34% incidenceof focalMRI abnormalitiesand a 17% incidence on CT. This is contrasted to a 71%incidence of focal EEG changes and a 59% incidence offocal abnormalities on interictal functional imaging measures (108). A few studies demonstrate a close relationshipbetween the severity of interictal ICBF reductions andeitherclinicalsymptomatologyor cognitiveimpairment(144). Homan et al. compared SPECT and neuropsychological assessments in 50 patients with partial seizures(145). Even though rCBF and neuropsychological deficits

were relatively mild in many patients, at least one lowflow region matched an area of neuropsychologically impaired function in 43 ofSO patients. There was a significantcorrelation between areas of visually identified hypoperfusion and neuropsychological impairment (p < 0.001).Stepwise discriminate function analyses revealed predictive relationships between deficits on specific neuropsychological tests and visually identified hypoperfusion, particularly in the left and right temporal regions. Similardata were reported by Berent et al. (146).

Pediatric StudiesSeizures in children may result from a variety of under

lying pathologies. There may be no relationship betweenclinical symptoms and either electrographic or radiographic findings, and the patients often have unpredictablecourses. Functional brain imaging could be useful in understanding clinical pleomorphisms associated with particular diseases, or as a device for subcategorizations usefulin predicting progression. Unfortunately, there are onlyseven published studies concerning functional brain imaging in pediatric epilepsy, excluding case reports andabstracts. Six of these involve PET (147â€”152)and one isan IMP SPECT study (153). The only clear conclusionthat may be drawn is that more work needs to be done. Itis likely, given the adult experience and the limited pediatric results, that functional brain imaging abnormalitieswill precede structural signs in infants and will likelyprovide an insight into observed seizure activity. Thelimited studies available for review suggest of a prognosticas well as a diagnostic role for functional brain imaging inpediatric patients, but such a role is not yet established.

PRIMARY BRAIN TUMORS

Malignant gliomas carry a dismal prognosis due to theiraggressive biological behavior. Newer treatment modalities, however, including radiosurgery and brachytherapy,have resulted in increased local control and survival rates(154). With aggressive treatment, an increasing number ofpatients will present with symptoms and signs that maybe secondary to recurrent tumor or to radiation changesalone. Establishing the cause of clinical deterioration inmalignant glioma patients treated with high dose radiation

1896 The Journal of Nudear Medicineâ€¢Vol.33 â€¢No. 10 â€¢October1992



is necessary for determining appropriate management.Progressive radiation necrosis requires surgical debulking,while solid tumor recurrence may require adjuvant therapy. CT and MRI are nonspecific and cannot distinguishradiation necrosis from treated tumor (155,156). EvenCT-guided biopsy may be unreliable. While PET has beenuseful to assess tumor viability and to differentiate recurrent glioma from radiation change (15 7), it is not readilyavailable in most medical centers.

Thallium-20l localizes in primary and metastatic braintumors (158). Its mechanism of uptake is unknown, butmay involve transmembrane transport into viable tumorcells (159). When 201Tl tumor uptake was compared toactivity in the contralateral hemisphere, high-gradegliomas were differentiated from low-grade lesions (160,161). Since this distinction has both prognostic and therapeutic implications, preoperative 201TlSPECT may aidin the timing of biopsy or surgery.

Combined 2oI'fl/99mTcHMPAO SPECT is useful fordiscriminating radiation changes from tumor necrosis asthe cause of clinical deterioration in patients with malignant glioma who have also been treated with high doseradiation. While 20Tl-chloride scintigraphy is highly sensitive for identifying recurrent tumors (162), in our experience it is insufficiently specific to be clinically useful byitself (163). When combined with 99mTcHMPAO however, three patterns of uptake can be identified. Highthallium activity (a tumor-to-scalp ratio of greater than3.5) is highly predictive of solid tumor recurrence in thesepatients (Fig. 9). When the thallium activity ratio is moderateor low (lessthan 3.5) and 99mTcuptakeis alsolow(less than 50% ofcerebellar activity), the likelihood of solidtumor recurrence is low. In those patients with moderatethallium uptake and high perfusion, SPECT is not predictive of either tumor or reactive tissue. This method mayalso prove useful for identifying the appropriate target forstereotactic biopsy excision or ablation once the SPECTand structural image are accurately merged (25).

PSYCHIATRIC DISEASE

SPECT applications in psychiatric disorders are not yetclinically useful. We have not yet discovered diagnostic orprognostic functional abnormalities in the major psychiatric diseases. However, SPECT may be of value in identifying unsuspected functional lesions. SPECT may alsobe useful to rule out organic complications not evident onother diagnostic tests. Promising research into mood disorders, schizophrenia and anxiety disorders suggests thatdiagnostic and prognostic roles for SPECT may soonemerge.

DepressionTwenty studies in the last 10 years found alterations in

cerebralperfusionor metabolismin depressedsubjects(164-183). Others have reported on effects of medication,electroconvulsive therapy and cognitive tasking in suchpatients (184â€”188).Unfortunately, findings are inconsistent. There are numerous reasons, including error due tosmall samples, variations in age and gender distribution,diagnostic heterogeneity, study conditions, severity ofdepression, and medication status. However, there areconsistent indications ofreduced global blood flow (gCBF)or glucose metabolism (gCGM), particularly in patientswith major depressive disorder (MDD), and possible reductions in the basal ganglia in both bipolar depressedphase (BP) and MDD samples. There are also suggestionsofalterations in the anterior-to-posterior gradient. Studieshave reported a relationship between cerebral biochemistryand symptom severity. Baxter recently suggested an emerging consensus for involvement oflateral prefrontal cortex,noting decreased rCGM in lateral prefrontal cortex indepression and elevated rCGM in orbital cortex in obsessive-compulsive disorder (OCD) (189). While some conceptual consensus is developing, firm conclusions wouldbe premature. For example, striatal abnormalities, whilereportedfor both disorders,have not beenconsistentlyidentified.

One explanation for the diversity of findings seen in theexisting literature is that no single region of the braindistinguishes depressed individuals from controls or isconsistently related over time to the symptomatology observed in depression. For example, Sackeim et al. foundthat an interacting network of regions explained the topographic distinctions between their BP patients and normal controls and that these regional effects existed separately from global alterations (181 ). Also, Devous et al.recently compared â€˜33XeSPECT in rCBF in 48 symptomatic MDD patients (13 nonendogenous, 24 endogenousand 11 psychotic) to 48 age- and gender-matched normalcontrols (188). Results revealed a significant age-by-depressive subtype interaction for gCBF and for rCBF ratios.Age effects on rCBF differed not only by region but alsoamong the three diagnostic subtypes. These findings of ageeffects among depressive subgroups are only one indicationofthe heterogenous nature ofthe population. For example,

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the notion of global reductions in cerebral blood flow indepression has been both supported and opposed. Such adiversity of results may be explained by examining theendogenous/nonendogenous and psychotic/nonpsychoticpatient mixtures in each study.

ObsessiveCompulsiveDisorderPET studies have revealed abnormalities in glucose met

abolic rates in obsessive compulsive disorder (OCD) patients, but the implicated areas vary from study to study.Baxter et al. have found increased metabolism in thecaudate nuclei, orbital gyri, hemispheres and orbital gyrusto-hemisphere ratio bilaterally ( 190, 191 ). Nordahl et al.did not report global, hemispheric or caudate abnormalities, but did find increased orbital frontal metabolismbilaterally and decreased right parietal and left parietooccipital metabolism in OCD as compared to normals(192). Another conflicting study reports increased metabolism in the right prefrontal cortex and in the left anteriorcingulate (193). A 33Xe SPECT study in 14 OCD patientsfound significantly lower mean blood flow, but no regionaldifferences between OCD and matched normals (194).Similarly, Nordahl et al. found lower glucose metabolicrates in OCD than in normal controls in most brainregions.

SchizophreniaRecent reviews suggest that SPECT and PET, as well as

the nonimaging â€˜33Xeinhalation probe technique, provideevidencefor frontallobedysfunctionin certainsubtypesofschizophrenia (195,196). While hypofrontality has beenreportedfrequently(197â€”200),not all investigatorshaveobserved it (201â€”203). Inconsistent findings have beenattributed to variability in study populations with regardto age, duration of disease, clinical state, subtyping (especially along the paranoid/nonparanoid dimension) andmedication status (204-208). Frontal lobe dysfunctionmay be more evident during the performance of cognitivetasks designed for frontal lobe activation (197,199,207,209â€”213). Hypofrontality also appears to be associatedwith the negative symptoms of schizophrenia (195,199).Temporal lobe abnormalities have also been reported (199,209,214). The combination ofboth anterior and posteriorfunctional alterations is often expressed as an abnormalityin the anterior/posterior gradient. Buchsbaum et al. andothers have also reported subcortical abnormalities, particularly on the left side (198,203,21 7â€”221).Generalized lefthemispheric dysfunction (laterality) has also been reported(195,203,204,222).

HEAD INJURY

Traumatic brain injury has an overall incidence similarto that of stroke, with a particularly high mortality in thefirst 48 hr post-trauma (223). Proper management of thesepatients requires an accurate assessment of underlyingbrain function and, consequently, emission computed tomography has been investigated as a possible monitor.

Technetium-99m-HMPAO SPECT has been shown to bemore sensitive than CT in detecting abnormalities in patients with a history oftraumatic brain injury, particularlyin the minor head injury group (223). Thus, 42 patients(80%)showedrCBFdeficitswithSPECTcomparedwith29 patients (55%) with CT. In addition to its highersensitivity, SPECT reflects changes in perfusion at anearlier time than CT (224). In a preliminary study, patientswith large lesions, multiple defects and lesions involvingthe brain stem appeared to have a worse prognosis thanthose patients with nonfocal, small lesions, particularly ifthey involved frontal or occipital lobes. SPECT may alsopredict the degree ofpermanent damage and those patientswho will develop post-traumatic headache (225). Roper etal. has shown that with HMPAO SPECT some patientswith traumatic brain injury may have cerebral blood flowequal to that of surrounding brain (226). This information may be of prognostic value or may simply indicateluxury perfusion with disassociation between metabolismand flow. At this point, the number of studies of SPECTand traumatic brain injury are small and involve only afew patients, but this application appears promising.

NEURORECEPTOR IMAGINGNeuroreceptor imaging now plays a very limited role in

clinical practice. Early clinical trials and the much largerPET experience suggest that useful applications willemerge and that a wide spectrum of radioligands willbecome available. SPECT ligands have been developed formuscarinic cholinergic receptors (â€˜231-3-quinuclidinyl-4-iodobenzilate, IQNB), the dopamine D-2 receptors ([1231]iodobenzamide, IBZM), the serotonin-2 receptor ([123!]iodoketanserin) and the benzodiazepine receptor (â€˜23I-Ro16-0154m, lomazenil).

The dopaminergic system plays an important role inthe coordination ofnormal brain function and is a primaryaction site for neuroleptic drugs for treating schizophreniaand Parkinson's disease. Furthermore, a number of centralnervous system diseases, including schizophrenia, tardivedyskinesia, Parkinson's disease and Huntington's chorea,are associated with changes in dopamine receptor densityin the brain. Iodine-l23-IBZM has been imaged in humansand has a distribution similar to that of positron-labeledD-2 receptor antagonists with localization primarily in thebasal ganglia (227).

lomazenil is a specific ligand for benzodiazepine receptors in the human brain (228). The highest concentrationofthis receptor antagonist is in the medial occipital cortex.lomazenil distribution is altered in partial epilepsy and, inearly qualitative imaging studies, appears to be abnormaleven when perfusion studies are normal.

Iodine-l23-IQNB studies of muscarinic acetylcholinereceptor binding in patients with Alzheimer's disease resultin images which are similar or less abnormal than imagesof perfusion in the same patients with Alzheimer's disease(229,230). Studies of the muscarinic acetylcholine system




are currently limited by nonspecific ligands such as IQNB,which label most or all of the muscarinic receptor sitesand cannot differentiate presynaptic from postsynapticbinding.

A number of problems will have to be overcome ifSPECT imaging is to play an important role in the assessment ofneurotransmitter function. High spatial resolutionwill be necessary to quantify absolute tracer concentration.While receptor affinity can be determined from relativemeasurements ofradioactive concentrations (231), carefulmodeling will be necessary to account for radiotracerkinetics and the effect ofblood flow on tracer distribution.It is possible, however, that scintigraphic imaging alonemay provide enough information to be diagnostically useful, as it has been with perfusion imaging. Furthermore,many neurotransmitters bind to a family of receptors.Unless ligands are developed for specific receptor sites, thefull value of this method will not be realized.

CONCLUSION

Substantial literature has emerged over the past decadecharting potentially powerful applications of functionalbrain SPECT in cerebrovascular disease, dementia, epilepsy, cancer and psychiatric disease. Nevertheless, its full

TABLE IWidelyAcceptedUsesofBrainSPECT

Alzheimer'sdiseaseAcutestrokeTransientischemicattacksEpilepsyRecurrent primarytumorHeadtrauma

TABLE 2Potential Applicationsof Brain SPECTCerebrovasculardisease

Delineation of stroke subtypesCerebrovascularreserveStrokeprognosisStrokeriskSubarachnoidhemorrhageprognosis

DementiaAIDS dementia complexHuntington'sdiseaseDementiaseverity, prognosis and treatment

PsychiatricdiseaseSchizophreniaDepressionAnxietydisorders

Parkinson's diseaseSubstance abuseCNS involvementin systemic disease

ChronicfatiguesyndromeLupusOthers

Pharmacologicand cognitivechallenge tests

potential as a diagnostic tool will emerge only when clearlydefined applications demonstrate scintigraphic findingswhich facilitate critical management decisions. Such applications are now beginning to emerge (Table 1) andmore will become evident as well-designed clinical trialsof efficacy and patient outcome establish its utility (Table2). Functional tests such as perfusion SPECT require care

ful and imaginative investigations to determine the properdiagnostic role of the physiological information that theyprovide as well as close cooperation between nuclear medicine physicians and their clinical colleagues to assure thatthe most relevant clinical questions are being answered.Properly approached, functional SPECT provides a uniquewindow to explore the hemodynamic and biochemicalconsequences of diseases that affect the brain.

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1992;33:1888-1904.J Nucl Med. B. Leonard Holman and Michael D. Devous, Sr. Functional Brain SPECT: The Emergence of A Powerful Clinical Method

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