Single Photon Emission Computed Tomography Brain Imaging

1042-3680/96 $0.00 + .20

CEREBRAL BLOOD FLOW

SINGLE PHOTON EMISSION COMPUTED TOMOGRAPHY BRAIN IMAGING Brian P. Mullan, MD, Michael K. O'Connor, PhD, and Joseph C. Hung, PhD

Although nuclear medicine brain imaging did not come of age until the routine use of technetium-99m brain perfusion tracers, attempts to measure brain blood flow with nonnuclear techniques were documented in 1948 by Kety and Schmidt109 who used nitrous oxide to measure brain blood flow. It was not, however, until the availability of satisfactory imaging systems such as the rectilinear scanner and later the Anger scintillation camera that there was further interest in brain imaging. 5 Later it was noted that brain blood flow was an indirect estimate of cerebral activity when Ingvar and Risberg96 observed changes in cerebral blood flow (CBF) with mental effort. The introduction of technetium-99m pertechnetate (Tc-99m) into nuclear medicine heralded the development of a number of radiopharmaceuticals that mapped the integrity of the bloodbrain barrier (BBB) and were imaged by planar scintigraphy with dynamic and static views. The subsequent development of X-ray computed tomography virtually overnight eliminated the need for most nuclear medicine BBB imaging studies. Advances in gamma camera technology such as the introduction of single photon emission computed tomography (SPECT) and new tracers capable of mapping cerebral perfusion have led to a resurgence of interest in nuclear medicine brain imaging.

This review examines the radiopharmaceuticals available for brain perfusion imaging, the technical aspects and developments of gamma cameras, and the clinical applications where these advances may have a role. TECHNICAL ASPECTS

In nuclear medicine, imaging of the brain can be accomplished either by positron emission tomography (PET) or SPECT. Although these two imaging techniques previously have been characterized by significant differences in technology and cost, recent advances in detector design now permit the use of a single instrument for imaging radiopharmaceuticals emitting either single photons or positrons. SPECT is the dominant technique in use in nuclear medicine for imaging of the brain. Conventional gamma cameras acquire planar images of the brain, in much the same way as a conventional photographic camera would acquire a photograph of the head. To generate tomographic images, the gamma camera obtains a series of images of the brain from a number of different angles as it is rotated about the brain. Typically, 60 to 120 planar images of the brain are acquired over a 360° rotation

From the Section of Nuclear Medicine, Department of Diagnostic Radiology, Mayo Clinic, Rochester, Minnesota

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of the gamma camera. These planar images provide the raw material for the reconstruction of the tomographic images. The quality of the tomographic images is, therefore, ultimately limited by the quality of the planar imagesthat is, the resolution of the tomographic images can never exceed that of the planar images. The primary advantage of SPECT is that of any tomographic technique-the ability to view activity in a region of the body without the confounding effects of superposition of activity from overlying or adjacent regions. Tomographic data usually are reconstructed using a filtered back-projection algorithm. This algorithm requires the use of a ramp filter for accurate reconstruction of the tomographic data. This filter enhances image noise, hence it is usually necessary to reduce the image noise by means of smoothing filters such as the Hann, Butterworth, Metz, or Weiner filters. All of these filters allow the user to vary the degree of smoothing; however, too much smoothing will remove not only noise, but also valuable structural information, whereas too little filtration will result in noisy images that are difficult to interpret. The appropriate degree of filtration is difficult to quantitate, and is largely a subjective one. The resolution of the final tomographic images dep ends on a number of factors-the primary ones are the intrinsic resolution of the gamma camera and the resolution of the gamma camera collimator. In clinical studies, an additional factor- patient motion-often may be the limiting factor in determining overall im age resolution. Conventional gamma cameras have intrinsic resolutions of approximately 2.5 to 4.0 mm. The collimator, however, which is the equivalent of a lens in a photographic system, has considerably poorer resolution and is the weak link in the imaging chain. A standard high-resolution collimator is constructed of lead and resembles a honeycomb matrix of holes. The hole diameter and length are typically in the range of 1 to 2 mm and 25 to 30 mm, respectively, giving a resolution of 8 to 10 mm in air at a distance of 10 cm. Although collimator resolution can be improved by either reducing hole diameter or increasing hole length, the disadvantage is a loss in the sensitivity of the system. For example, improving collimator resolution from 8 mm to 4 mm leads to a 4-fold reduction in the number of counts acquired per unit time. Ultimately, if too few counts are recorded in

a study, the increase in statistical noise in the image data overwhelms any gain in resolution. As there is a practical limit on the length of time a patient can be expected to remain still during a study, and hence on the number of counts that can be acquired, this has limited the resolution achievable with conventional gamma camera systems. A number of approaches have been used to overcome this limitation. These include the use of dedicated brain imaging systems, dual or triple head gamma camera systems, and the use of innovative collimator designs. During the last 5 years, a number of dedicated brain imaging systems have been developed commercially. These include the Ceraspect system (Digital Scintigraphics, Waltham, MA), the Headtome system (Shimadzu, Tokyo, Japan), and the SME-810 (Strickman Medical Equipment, Medfield, MA). All three systems place detectors in a ring geometry around the head and hence can achieve a significant increase in sensitivity over conventional gamma camera systems. For example, the Ceraspect system can achieve a resolution of 5.5 to 6.5 mm in the brain, with a sensitivity four to five times that of a conventional singlehead system . On conventional detector systems, sensitivity can be increased through the use of multiple detectors. Dual- and triplehead systems will obviously increase sensitivity by an amount corresponding to the number of detector heads. This increase in sensitivity then can be used to offset the drop in sensitivity associated with the use of higher resolution collimators. In efforts to further increase sensitivity, manufacturers have turned to the use of innovative collimator designs, such as fanbeam and cone-beam collimation. The principle behind the use of these collimators is based on the fact that with a conventional parallel hole collimator, only that part of the gamma camera field of view directly in front of the head is used in imaging the brain. Fan-beam collimators act like a parallel hole collimator in the axial direction but are focused in the x-direction. This gives image magnification in the x-direction and allows more of the detector to "see" the head (Fig. 1). The degree of magnification and the resultant gain in sensitivity increases with decreasing collimator focal length. The shorter the focal length, the greater the gain in sensitivity; however, the focal length must be long enough to ensure that the entire brain is inside the field

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Figure 1. Comparison of parallel hole, fan-beam, and cone-beam collimation. Fan-beam and conebeam enhance sensitivity by magnifying the projection data onto a larger crystal area.

of view. In this respect, very large field-ofview systems (50-60 cm) can use shorter focal length collimators than standard 40-cm field-of-view systems. Compared with a parallel hole collimator with comparable resolution, fan-beam collimators can give a gain of up to two times in sensitivity while showing improved resolution at depth. 151 Figure 2 illustrates the potential gain in image quality that can be obtained with fan-beam collimators relative to conventional parallel hole collimators. Cone beam collimators are focused in both the x- and y-directions and potentially can offer a gain of three times in sensitivity over parallel hole collimators. 101 These collimators have

been shown to offer significant improvements in lesion detection, relative to parallel hole or fan-beam collimators. 137 Although cone-beam collimators present some technical challenges in terms of image acquisition and still should be considered in the development stage, these collimators may be in clinical use in the next few years. Although a number of very important and useful positron emitting radiopharmaceuticals have been developed during the last 10 years, the use of these agents in clinical practice has been limited by the high costs associated with PET imaging. Recent developments in gamma camera detector technology may increase the

Figure 2. Comparison of transaxial images of a Hoffman brain phantom acquired using single head system with high resolution parallel hole collimator (A) and dual-head system with ultrahigh resolution fan-beam collimators (B). The same acquisition time was used for both studies .

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potential use of these agents. These developments center around the increasing use of digital technology in the design of the detector and have led to the development of "digital" detectors. Although not truly digital (due to the continued use of analog photomultiplier tubes), these new detectors have improved significantly all aspects of system performance. In particular they have increased the speed with which events can be processed and permit the use of new algorithms for the determination of the location of gamma rays striking the detector. Using these new detectors, several manufacturers have now implemented coincidence imaging on dual-head systems that permits the removal of the collimator and the use of the system in coincidence mode, analogous to the method used by PET scanners. Initial results have indicated that in this mode, these dual-head systems can achieve similar resolution to conventional PET scanners, albeit with some limitations in terms of sensitivity and count rate capability. Figure 3 illustrates a comparison of an F-18 fluorodeoxyglucose study acquired on a PET scanner and on a dual-head system in coincidence mode. By eliminating the need to purchase a dedicated PET scanner, this new technology will increase

10 mCi F-18 FOG

the number of potential sites that can incorporate PET imaging into their clinical practice. With the increasing use of SPECT and PET imaging in clinical practice comes the need to develop methods of correlating the functional information present in these images w ith the anatomic information available in MR imaging and CT. In the research environment, a large number of techniques have been developed during the last 5 years that permit coregistration of the SPECT / PET images and those from MR imaging and CT. 4•30 Until recently, a significant obstacle in the co-registration of image data from different modalities was the difficulty in transferring the data to a common computer system. With the recent development of DICOM (Digital Imaging and Communications in Medicine), an international standard now exists for image data transfer between dissimilar systems. 1• 19 On systems that support this standard, it is possible to import and display data from different modalities. Concurrent with the implementation of DICOM, a number of vendors are implementing co-registration packages that will bring image fusion techniques into more widespread clinical use (Fig. 4). It is likely that further developments in this area will increase the ease with which data can be moved within

3.8 mCi F-18 FOG

Figure 3. Comparison of an F-18 fluorodeoxyglucose study acquired on a PET scanner (A) and on a dual-head gamma camera system (8) in coincidence mode. (Courtesy of ADAC Laboratories.)

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a network of systems, and the accuracy and speed with which co-registration can be performed.

CEREBRAL PERFUSION RADIO PHARMACEUTICALS

With the exception of a few cerebral disorders, regional cerebral blood flow (rCBF) generally is coupled or related to metabolism. This observation is the basis for the use of cerebral perfusion radiopharmaceuticals in brain SPECT imaging studies. The generally accepted criteria for the ideal SPECTbrain perfusion tracer are as follows: (1) free crossing of the intact BBB, (2) complete first-pass extraction from the blood into the brain, (3) proportional distribution to CBF, (4) long retention within the brain without redistribution and metabolism, (5) low radiation dose to patients, and (6) wide availability for routine studies. Unfortunately, only radiolabeled microspheres injected directly into the carotid artery completely satisfy these requirements. Although quantification of rCBF with Tc-99mand I-123-labeled SPECT radiopharmaceuticals can be achieved by arterial samp ling and careful modelin g to comp ensate the incomp lete extraction, back diffusion, and other deviations from the theoretical model,115 these so called "chemical microspheres" are not practical for routine evaluation of rCBF. Nevertheless, the SPECT radiopharmaceuticals used for brain perfusion imaging have for the most part fulfilled the rCBF criteria. In addition, most routine SPECT /CBF studies do not require quantitation of rCBF and only rely on the image acquisition that reflects radiotracer uptake and retention.

Radiopharmaceuticals for rCBF Measurements

Xenon is the original noninvasive rCBF marker first introduced by Mallet and Veall in 1965.141• 203 The noninvasive method involves the inhalation of the freely diffusible Xe-133 gas while the input function (rate of arterial delivery of the radiotracer to the brain) and the clearance of Xe-133 in each specific region of the brain are monitored with gamma detector probes. This method also could be used w ith SPECT imaging technique, which allow s

multiple rapid measurements of rCBF to obtain absolute quantitative data expressed in mL/min/ 100 g. The advantages of the Xe-133 inhalation method include multiple dosing, low cost, and low radiation d ose. Although Xe-133 has been considered the gold standard radiotracer for the measurement of rCBF there are several significant problems associated with the Xe-133 SPECT. l. The less than optimal gamma photon en-

ergy (80 keV) of the radioisotope and the fast w ashout of tracer from the normal brain tissue provide inferior spatial resolution. This not only makes evaluation of deep structures difficult but also restricts the minimum volume from which accurate measurements can be made.54 2. The inhalation technique (placement of the gas mask and the operation of the xenon delivery system) is technically more difficult than the intravenous method for cerebral perfusion radiopharmaceuticals. 3. The fast pharmacokinetics of Xe-133 necessitate the use of a highly sensitive rapidly rotating SPECT detector device capable of acquiring image d ata in a sh ort time frame ( <20 sec) in order to permit the evaluation of Xe-133 washout curves.147 4. Contamination of the clearance curves by radioactivity from the scalp and other extracerebral sources may contribute significant measurement error. Because of these problems, the Xe-133 SPECT method has had limited routine clinical use.

Other Radiopharmaceuticals for the Study of rCBF

The use of other radiotracers with slower clearance from the brain allows for an estimate of rCBF. These tracers do not satisfy com pletely the requirements for computing a CBF, but they mimic CBF closely enough to have clinical use. In addition, when imaging the CNS using SPECT, exact quantification of the rCBF generally is not needed . 1-iofetamine (Spectamine)

1-123-iofetamine, also known as 1-123-IMP (I-d, I-N-isopropyl-p-iodoamphetamine hydrochloride) (Fig. 5) w as the first lipid-soluble

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3 1-0CH2-CH- NH- CH/CH I ' CH3 CH3 Figure 5. Chem ical structure of 1-123 IMP.

brain-imaging agent approved by the US Food and Drug Administration (FDA) and was commercially available in the United States in 1988. This radiopharmaceutical was developed by Winchell and associates 212 at Medi-Physics, and was followed immediately by the development of another radioiodinated amine, I-123N,N,N' -trimethyl-N' -2-hydroxyl-3-methyl-5isobenzyl-1,3-propane diamine (I-123-HIPDM) by Kung and colleagues 118 at the State University of New York at Buffalo. It is thought that certain neurologic disorders are associated with some degree of alteration in amine kinetics or function. 60 The first two SPECT rCBF radiotracers were labeled with radioiodine because of the ease of incorporation of the iodine into biologically active molecules without concomitant loss of biologic activity. Both radioiodinated amines have fairly rapid brain uptake and good extraction. I-123-HIPDM has a brain retention half-life of 6 hours, whereas the retention of I-IMP is of shorter duration (60-90 min). I-123-HIPDM was never approved by the FDA and, therefore, is not commercially available in the United States. The distribution of I-123-IMP correlates with CBF over a wide range but may underestimate CBF when plasma pH is low (e.g., cerebral ischemia or acidosis).11 5 After intravenous administration of I-123-IMP, the brain image must be completed quickly as there is a substantial change in the I-123-IMP distribution in the brain as a result of its redistribution. The later redistribution of I-123-IMP has been suggested to be due to processes other than CBF. This agent had to be specially ordered from the manufacturer; therefore, its use in an emergency situation was restricted severely.60· 86 Although I-123-iofetamine was used extensively as a cerebral perfusion agent, it is no longer commercially available in the United States; the relatively high cost and limited availability (cyclotron-produced I-123) have encouraged the development of Tc-99mlabeled brain perfusion radiopharmaceuticals.142 The only prospect for its reintroduction

would be for dual isotope imaging with a Tc99m agent. Tc-99m-HMPAO (Tc-99m-Exametazime, Ceretec)

Hexamethylpropyleneamine oxime (HMp P,..O), is a Tc-99m optically active ligand (Fig. 6) for brain perfusion imaging, first FDA-approved in 1988. Volkert and colleagues204 at the University of MissouriColumbia and investigators at Amersham in Arlington Heights, IL,133• 156 jointly developed this agent, which has the advantages of a technetium label with a 140-keV monoener~etic photon, a reasonably short physical halfhfe of 6 hr, and is readily available from either on-site labeling or a commercial nuclear pharmacy. The primary complex d, 1-isomer of Tc-99mHMPAO (Fig. 6A), not the meso isomer (Fig. 6B ), is a lipophilic moiety that diffuses into the brain by crossing the BBB. The d, I-isomer o~ Tc~99n:-m':1PAO_ ~see Fig. 6A) shows very high m vivo mstabihty and prolonged brain retent_ion, whe.reas the meso isomer (see Fig. 6B) displays higher in vitro stability and little in vivo brain retention. 85 The d, I-Tc-99mHMP AO reacts in seconds with intracellular glutathione after intravenous injection to con:rert to a hydrophilic secondary complex that is no longer capable of diffusion back across the BBB.11· 155 Consequently, the radiotracer is trapped inside the brain. The maximum brain uptake of 3.6% to 7.0% injected dose occurs within 1 minute of injection.* Of the initial activity taken up in the brain, up to 15% of the brain activity washes out within 2 minutes post injection, after which there is minimal loss of radioactivity over the next 24 hours.* There is no redistribution of the lipophilic Tc-99mHMP AO between gray and white matter during the first hour after administration. The urinary excretion is 40% in 48 hours after injec* Ceretec package insert, Amersham Corp., Arlington Heights, IL, 1990.

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Figure 6. Chemical structure of the two isomers of Tc-99m HMPAO. A, Tc-99m d,1HMPAO; B, Tc-99m-meso-HMPAO.

tion.*The soft tissue, liver, and gastrointestinal uptake is high (10% to 30%).184 The blood clearance is slow after intravenous injection of Tc99m-HMPAO resulting in a blood level of 12% of the injected dose at 1 hour post injection.184 The slow blood pool clearance probably is related to the interaction of Tc-99m-HMPAO with glutathione present in red blood cells. Although Tc-99m-HMPAO has many optimal characteristics for rCBF studies, it does not behave like a "chemical microsphere." Therefore, quantification of an rCBF in units of mL / min/ g of tissue128 or by using other algorithms143· 171 has not been accepted universally or widely used. This lack of acceptance is mainly because of the following reasons: (1) incomplete first-pass extraction,55· 85 (2) the relatively low uptake in the brain, (3) rapid metabolism, (4) significant washout, (5) little knowledge of the intimate mechanisms of uptake and intracerebral retention, (6) the presence of high levels of different complexes in the circulating blood,140 (7) intracerebral distribution changed, and (8) variable amounts of free pertechnetate. In addition, significant back diffusion of unmetabolized lipophilic Tc-99mHMPAO from the brain to the blood results in poor image contrast between the normal region and the hypoperfused area. 214 Because of the "hyperfixation" of Tc-99m-HMPAO in the subacute infarct area,191 Tc-99m-HMPAO tends to overestimate the degree of hyperemia during luxury perfusion. In comparison w ith I-IMP, Tc-99m-HMPAO underestimates the lesion size determined by the I-IMP. This sug-

gests that Tc-99m-HMPAO and I-IMP mark somewhat different territories of damages in cerebrovascular disease. Although Tc-99m-HMPAO was a major breakthrough for the brain perfusion study, rapid decomposition of the labeled compound in vitro requires its use within 30 minutes of preparation.* This affected the ability to perform true ictal epilepsy studies using Tc-99mHMPAO. In 1995, a new stabilized formulation of Ceretec was approved by the FDA. The original lyophilized content of the Ceretec vial was unchanged, the extended stability (from previous 30 min* to 4-6 hr post reconstitutiont) is achieved by the addition of methylene blue and sodium phosphate solution. The package insert for the preparation of stabilized Tc-99mHMPAO recommends that up to 2.0 GBq (54 mCi) of Tc-99m may be added to the vial.t With the introduction of the stabilized form of Tc-99m-HMPAO, the limitation for imaging patients w ith seizure disorder with this agent (especially for the ictal study) should be eliminated. Clinical experience with Tc-99m-HMp AO also has been documented in patients with Alzheimer's dementia,91 · 147 a variety of psychiatric disorders,147 brain death,124· 13o, 147 epilepsy174· 175 and trauma. 38 Clinical use of the new stabilized version may in time lead to additional neurologic indications for the use of the stabilized Tc-99m-HMPAO. * Ceretec package insert, Amersham Corp., Arlington Heights, IL, 1990. t Ceretec package insert, Amersham Corp., Arlington Heights, IL, 1995.

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Tc-99m-ECD (Tc-99m-Bicisate, Neurolite)

Tc-99m-ethyl cysteinate dimer (Tc-99mECD) is a neutral lipophilic complex localized in the brain by crossing the intact BBB. Tc-99mECD belongs to the N 2S2series, which was originally suggested by Kung and associates.11 9 This radiopharmaceutical then was developed as a brain SPECT imaging agent in humans. 135 Tc99m-ECD is an optically active ligand in which the L,L-isomer (Fig. 7) shows the desired brain uptake and prolonged retention whereas the D,D-isomer also displays high initial brain uptake but the retention is disappointing. 206 This new radiopharmaceutical was approved by the FDA in late 1994 and was approved for SPECT imaging as an adjunct to CT or MR imaging in the localization of stroke in patients in whom "stroke has already been diagnosed.":!: The package insert of Neurolite further states that Tc-99m-ECD "is not indicated for assessment of functional viability of brain tissue. Also, Neurolite is not indicated for distinguishing between stroke and other brain lesions.":!: From the information listed here, it would appear that the approved indications for usage of Tc-99m-ECD are limited; however, this has not prevented its use for physician-directed nonapproved indications such as epilepsy and dementia. The brain retention mechanism is based upon the very rapid conversion of the lipophilic form to a water-soluble acid that is too polar to diffuse out of the brain. This conversion process is assumed to be a specific hydrolysis of one of the ester groups of Tc-99m-L,LECD and the de-esterification process is a very specific enzymatic reaction. 206 It seems that this enzyme is distributed ubiquitously throughout the brain. 128 It has been suggested that the rate-limiting step for retention of Tc-99m-ECD in the brain is the delivery rate via passive diffusion through the BBB and not the enzymatic conversion. 128· 206 The study on retention of Tc-99m-ECD in the human brain by Friberg et al, however, demonstrated that this enzymatic conversion is not instantaneous and that there is a considerable initial back diffusion and washout of Tc-99m-ECD from the brain. 128 Tc-99m-ECD has moderate cerebral extraction and underestimates CBF similarly to Tc99m-HMPAO. After intravenous injection, Tc:j: Neurolite package insert, DuPont, Billerica, MA, 1994.

Figure 7. Chemical structure of Tc-99m-L,L-ECD (A) and Tc-99m-D,D-ECD (B).

99m-ECD shows rapid brain uptake, which amounts to 5% to 7% of the injected dose at 5 minutes postinjection with very slow washout.+ Unlike Tc-99m-HMPAO, which experiences a rapid washout of the original brain uptake, Tc-99m-ECD is retained in the brain with little change for at least 20 minutes after injection.90· 135 Initial washout from the brain is estimated to be 12% to 14% in the first hour compared with 15%washoutofTc-99m-HMPAOin 2 minutes. 90 • 156· 202 Like Tc-99m-HMP AO, there is little redistribution within the brain for Tc99m-ECD. The blood clearance ofTc-99m-ECD is very rapid, and the blood activity is less than 10% after 5 minutes. 134 Tc-99m-ECD is excreted primarily through the kidneys, and the urinary excretion is 50% in 2 hours and 74% in 24 hours after injection,* whereas only approximately 40% of the injected dose of Tc-99m-HMPAO is excreted through the kidneys and urine over the 48 hours after injection.f Only 12.5% of the injected dose of Tc-99m-ECD compared with more than 50% of the Tc-99m-HMPAO dose is eliminated through the gastrointestinal tract after 48 hours.*·t With the exception of the brain Tc-99mECD has a more rapid washout from all organ tissues and blood compared with Tc-99mHMP AO and allows not only less radiation exposure to the patient but also a higher brain-to-background contrast ratio than with * Neurolite package insert, DuPont, Billerica, MA, 1994. t Ceretec package insert, Amersham Corp., Arlington Heights, IL, 1995.

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Tc-99m-HMPA0. 134• 147 SPECT image quality comparing I-123 IMP, Tc-99m-HMPAO, and Tc-99m-ECD shows that the image contrast (i.e., lesion-to-normal contrast and gray matter-to-white matter contrast) of Tc-99mECD is less prominent than that of I-IMP, but is better than that of Tc-99m-HMPA0.202 Recent studies with Tc-99m-HMPAO, however, demonstrated that equivalent contrast can be obtained 90 minutes post injection of Tc-99m-ECD. 44 Another comparison study of Tc-99m-ECD and Tc-99m-HMPAO in diagnosis of chronic stroke and dementia33 demonstrated that both agents have similar diagnostic accuracy and general distribution in the brain in accordance with rCBF; however, this study was performed in a limited patient population. Unlike Tc-99m-HMPAO, which shows an abnormal degree of retention in subacute infarcts (luxury perfusion), Tc-99m-ECD is poorly retained in the developing infarct and thus does not show reflow hyperemia and, therefore, does not mask the size and the severity of the brain lesion as may happen with the Tc-99m-HMPA0.125 Tc-99m-ECD is more stable in vitro after kit formulation (i.e., 6 hr for Tc-99m-ECD vs. 4-6 hr for stabilized Tc-99m -HMPAO).*· t There is no restriction as to the ingrowth time or age of the Tc-99m generator eluate to be used for reconstitution of the Neurolite kit, and up to 3.7 GBq (100 mCi) of Tc-99m-sodium pertechnetate can be added to the kit (the package insert of Ceretec only allows up to 2.0 GBq [54 mCi] of Tc-99m to be added to the vial).*· f The procedures for preparation (i.e., 30-min incubation) and RCP determination (i.e., 3555 min), however, would not allow the immediate on-site preparation of Tc-99m-ECD for ictal patient studies.* We have developed a simple and rapid method for the preparation and quality control of Tc-99m-ECD.31• 94 By using a microwave oven at a low heating cycle and single mini-paper chromatography, Tc99m-ECD can be prepared in 8 seconds, and the radiochemical purity analysis can be completed in 3 to 4 minutes. At present, the cost ratio between the cold kits of Neurolite and Ceretec is approximately 1.4. This cost ratio, however, may be reduced to approximately 0.7 because the Neurolite kit allows almost twice the amount of Tc-99m activity.*· t * Neurolite package insert, DuPont, Billerica, MA, 1994. t Ceretec package insert, Amersham Corp., Arlington

Heights, IL, 1995.

CLINICAL APPLICATIONS OF BRAIN SPECT General Considerations It is important to have a standard method of evaluating and interpreting brain perfusion studies. The interpretation ideally should be initially blinded to the clinical situation but this should be available for the final interpretation. The brain study should be reconstructed in the usual three orthogonal slices, transverse or axial, coronal, and sagittal projections. Additionally, there may be need to review offset transverse and coronal slices as in temporal lobe epilepsy. A three-dimensional rotating display of the surface anatomy is often helpful in visualizing cortical defects but conveys little information regarding the deeper structures. It is recommended that the images be reviewed or reported on a high-quality computer monitor in a black and white gray scale rather than using the hard copy images as their quality can be variable. A color display can be useful for simple review and often is u sed for paper reports but does not have the d ynamic range that is present with 255 gray scale levels. In the authors' experience useful color look-up tables include "hot iron," "rainbow," and "heart" color scales. A sound knowledge of the normal appearance and neuroanatomy with reference to any available anatomic imaging study such as CT and MR imaging is important for interpretation of SPECT brain studies. Additionally, it is widely accepted that regional brain blood flow is heterogeneous and side to side variations should be thou ght of as significant only if they exceed 10% to 13%. This therefore implies a need for brain quantitation when reading these studies. Cerebrovascular Disease

Background

With an incidence of 2 per 1000, cerebrovascular disease is the most common neurologic disease. It is a significant cause of death and morbidity, ranking third after heart disease and cancer, and is the second most common cause of dementia. In the United States, there are more than 400,000 stroke cases per year, most of whom undergo anatomic imaging such as CT or MR imaging. Cerebrovascular disease may present a varied disease spectrum

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with such entities as stroke, whether embolic, thrombotic, or hemorrhagic; transient ischemic attack (TIA); subarachnoid hemorrhage (SA); arteriovenous malformations (A VMs); vascular dementia; and other rarer abnormalities such as moya moya disease. From this list, the clinical situations in which brain SPECT may contribute to patient care are the detection of acute ischemic events and their possible causes, the assessment of prognosis or clinical outcomes, monitoring progress of intracranial hemorrhage, and assessment of transient ischemic attacks. There also may be a role in the quantitation of salvaged brain following acute therapy. Regional and global CBF estimation has been possible for many years with Xe-133/ probe systems and PET tracers such as 0-15 water and N-13 ammonia. These have contributed to the understanding of the pathophysiology of cerebral ischemic events. Measurements of regional cerebral blood flow (rCBF), regional oxygen extraction fraction (rOEF), regional metabolic rate of oxygen (rCRM02), and rCBV have characterized the sequence of physiologic changes that occur with reductions in cerebral perfusion pressure. The ratio (CBF I CBV), normally in the order of 10:1, is taken as an index of cerebral perfusion pressure and is under autoregulatory control. The inverse relationship CBV /CBF implies the mean transit time. The effects of stroke which often occurs suddenly and without warning are in part determined by hemodynamic variables, the extent of the flow interruption, the presence or absence of collaterals, and the amount of prior ischemic damage. Patients may also experience a chronic low flow state (misery perfusion), which can lead to alterations in the rCRM0 2, rCBF, rCBV, and rOEF. Initially, a reduction in cerebral perfusion pressure leads to compensatory vasodilatation (increasing rCBV) to preserve rCBF. A further decline in the flow rates results in an increase in the rOEF, which serves to maintain rCMR0 2• Subsequent perfusion pressure reductions without additional compensatory measures results in physiologic neuronal and structural changes. A critical ischemic CBF threshold of 17 mL/min/ 100 g appears to exist before irreversible cerebral cortical damage occurs. 164 The use of SPECT tracers to map these physiologic variables (rCBF) was enhanced with the use of Xe-133 SPECT but, although this provides quantitative and regional data,

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it is demanding and is limited technically because of poor spatial resolution and reduced count rates. More recently, Tc-99m products such as HMPAO, ECD, and labeled red blood cells (RBC) as well as I-123 IMP have been able to address some of these questions. For instance the combination of I-123 IMP and Tc-99m RBCs can provide an index of rCBF I rCBV or cerebral perfusion pressure and reserve now that modern gamma cameras can image these two isotopes simultaneously. A more convenient way of assessing cerebrovascular reserve is with the use of intravenous acetazolamide as is discussed in another section. Evaluation of Stroke

Stroke can be categorized broadly into events caused by focal ischemia (70%), intracerebral hemorrhage, (20%), and SA (10%). The development of new and promising therapies for acute stroke has precipitated the need for prompt and accurate assessment of rCBF. rCBF measurement in patients with cerebrovascular disease was the earliest application of SPECT brain imaging reported by Ell et al55, who used HMPAO in patients with acute stroke. It is already widely accepted that the current anatomic imaging devices do not characterize acute changes in CBF, that is, those that occur within the first few hours of the event. By 8 hours following cerebral infarction, the CT scan will be positive in only 20% of cases, 26• 65 compared with more than 90% of SPECT studies showing abnormalities over a similar time span. These, however, relate to cortical abnormalities, and the sensitivity for subcortical damage is significantly lower. 41 • 169 This does not diminish the need or requirement for CT in the acute evaluation of stroke as it can document reliably the presence or absence of intracerebral hemorrhage, which is critical if thrombolytic therapy is being considered. MR imaging as routinely performed currently is not sufficiently sensitive to document CBF alterations in the very early phase of acute stroke,3 but will indicate hemorrhage. Newer developments, however, may improve the utility of MR imaging in acute stroke. The sensitivity of brain perfusion SPECT to localize ischemic stroke was examined by two large blind prospective studies, and was acceptable at 61 % to 74%, somewhat higher

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A Figure 8. SPECT brain perfusion images showing left middle cerebral artery stroke. A, Coronal images. B, Transverse images. Illustration continued on opposite page

for the nonlacunar strokes (85%), and the specificity was high, ranging from 88% to 98%. 27 This is one potential indication for the use of brain radionuclide SPECT imaging, namely in the acute evaluation of stroke-like symptoms and signs for which the initial anatomic imaging study is negative. Figure 8 is an example of a SPECT image of a completed stroke. The Tc-99m HMPAO brain study must be interpreted with caution in the period from 5 to 20 days after the acute event as there may be luxury perfusion, which can spuriously show increase or return of perfusion to the infarct zone.152• 191 It is thought to be caused by dysautoregulation with uncoupling of perfusion and metabolism or possibly later caused by capil-

lary hyperplasia. It is also known to occur with 1-123 IMP but not with Tc-99m ECD. 127• 200 It also has been observed with Xe-133 and PET brain studies. 124• 213 Luxury perfusion should be distinguished from patients who have a component of cerebral edema that can appear to show increased CBF on SPECT but in reality it is normal flow to compressed brain that appears more intense than the surrounding brain further contrasted as it often occurs at the edges of infarcts or areas of reduced flow. Figure 9 is an example of luxury perfusion. There is evidence that very early reperfusion can occur with acute stroke and may convey a better prognosis compared with luxury perfusion occurring in the latter time period.105• 186 Crossed cerebellar diaschisis often is present in stroke

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B Figure 8 (Continued).

patients with significant depression of cerebral neuronal function and metabolism and is seen as reduced perfusion and metabolism in the contralateral cerebellar hemisphere. 146· 152· 167 As crossed cerebellar diaschisis persists in patients with luxury perfusion it potentially may aid in the interpretation of studies in which luxury perfusion is considered a problem.120· 166 Figure 10 is an example of crossed cerebellar diaschisis associated with stroke. Prognosis Mountz et al1 53 proposed evaluating the extent (volume) of the perfusion abnormality correlating it with the CT abnormality and were able to show that the patients with greater perfusion change than CT abnormality would show clinical improvement in followup.153 This differential zone may be due to a

diaschitic effect, ischemia, or selective neuronal loss and possibly potentially recoverable functional tissue. Matsuda et al1 44 further assessed this by acetazolamide given to patients to distinguish diaschisis from ischemia or selective neuronal loss. 144 Although SPECT has given mixed results in predicting outcome, a number of studies have shown that outcome is related to the acute perfusion changes, large perfusion defects correlating with poor outcome.63· 70· 138 Prognostic information also has been derived with SPECT from activation studies such as the Boston Naming Test outlined by Tikofsky and Hellman, 198 regarding recovery of speech following stroke. Characterizing stroke subtypes may be important to allow the application of newer therapeutic options as well as providing informa-

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Figure 9. Tc-99m HMPAO SPECT brain perfusion image showing luxury perfusion; the top row is transverse images and the bottom row is coronal images. Left side, Images performed 6 days following a left middle cerebral artery stroke; right side, Images performed 10 weeks later. The white arrows indicate the site of luxury perfusion in the initial images.

tion regarding the likelihood for recurrence, recovery, or death.21' 178' 181 Anatomic imaging is somewhat limited in this regard and could indicate a role for brain perfusion SPECT. 56 Patterns of peripheral or distal field infarction can be seen earlier on SPECT as compared with CT or MR imaging. 8' 41' 165 Although not pathognomonic, embolic strokes tend to have wedge defects and the lack of a cortical defect argues in favor of a lacunar stroke.28, 41 Being able to characterize the extent of the perfusion abnormality also may have a function in tailoring therapy. The clinical utility of acute stroke imaging has been enhanced by the availability of stable perfusion tracers such as Tc-99m ECO and more recently Tc-99m HMPAO. For these to be clinically useful they must be available to the end user in a timely manner, for instance in the emergency room such that the patient

can be injected during symptoms and imaged at a more convenient time, perhaps following anatomic imaging. Additionally, if the time for imaging is considered problematic there is evidence that shorter acquisition times will provide diagnostic images in a more timely manner than the current 30 to 40 minutes, particularly if a multihead camera is u sed.112, 163 Having the radiopharmaceuticals available in the emergency setting will then allow use of the SPECT data for stroke intervention trials and, as it has been shown, knowing the extent of perfusion deficit can be predictive of functional recovery.74 Repeating the study after therapy can allow the assessment of salvage as well. 9, 82 This would require having a reliable and reproducible method for brain quantitation. All of these scenarios are akin to the way that Tc-99m sestamibi can used in the assessment of patients presenting to the emergency

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Figure 10. SPECT brain perfusion image showing crossed cerebellar diaschisis affecting the right cerebellar hemisphere (solid white arrow). This was caused by a left posterior parietal infa rct (curved dotted arrow) .

room with chest pain and suspected myocardial infarction. 69 • 148 Cerebrovascular Reserve It is pertinent to consider the role of SPECT in the evaluation of cerebrovascular reserve. As previously mentioned this can be inferred from the rCBF I rCBV ratio but this is somewhat complicated. A simpler approach has been developed utilizing acetazolamide. This agent crosses the BBB and is an inhibitor of the enzyme carbonic anhydrase resulting in increased PC0 2 levels with consequent increase in CBF. A dose of 1 g given intravenously results in peak CBF increase stimula-

tion (approximately 30%- 60%) within 20 minutes at which stage the brain tracer must be injected. The same effect can be achieved by inhaling air with approximately 5% C0 2•34 To assess these changes, comparison with a resting or baseline study and quantitation is often crucial as gross changes in the lack of vasodilatory reserve can be quite obvious visually but subtle d ifferences may not be readily appreciated. Although this is an excellent test, it does suffer from some limitations because of the lack of linear response of the brain uptake compared with the absolute flow changes. The study can be considered the "brain stress test" and is analogous to the use of dipyridamole and adenosine in the assessment of myocardial

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flow reserve. The measurement of vascular reserve potentially can be helpful in the evaluation of stroke, TIAs, and AVMs, and in assessing the significance of carotid lesions and moyamoya disease, and possibly in studying Alzheimer's and vascular dementia. Figure 11 is an example of poor cerebrovascular reserve. Transient /schemic Attacks

The structural evaluation of TIA patients with CT is of limited benefit although it may show possible hemorrhage. 37 Medical evaluation for cardiac sources of emboli, carotid vascular disease, and hematologic precipitants such as polycythemia is important in identifying the cause of a TIA. SPECT can provide valuable information as to the nature of the event but its sensitivity is time dependent as

60% are positive on the first day compared with 40% on day two and falls further in subsequent days.41 • 75 The use of acetazolamide has been shown to improve the sensitivity of SPECT in evaluating TIA. 35 • 47 The likelihood for future completed stroke in the next week is high if there is persistent reduction in rCBF (> 30%) days after the event. 22 In this fashion, SPECT may prove prognostic. Subarachnoid Hemorrhage (SAH)

SAH accounts for about 10% of all strokes generally affecting a younger population. If the initial event is not fatal there are a number of complications that may develop during recovery such as vasospasm, edema, recurrent hemorrhage, increased intracranial pressure, and hydrocephalus. Vasospasm, which usu-

Figure 11. SPECT brain perfusion image showing abnormal cerebrovascular reserve. The top row are transverse images, middle row sagittal images , and the bottom row are coronal images. The left panel show the images following acetazolamide with the resting or nonacetazolamide images in the right panel. There is marked right parietal, temporal , and to a lessor extent, frontal asymmetry with acetazolamide (reduced perfusion) that returns to normal in the right or resting images.

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ally occurs after the first week, results in decreased rCBF and metabolism with increased CBV and may cause further cerebral damage and death. 87• 104 It is estimated that vasospasm occurs in 30% of patients and that of those graded as severe, 80% go on to develop a clinical deficit from ischemia in that territory.10 The definitive diagnosis depends on cerebral angiography documenting vascular narrowing; however, this is invasive and potentially can precipitate or exacerbate the event. Transcranial Doppler sonography also can evaluate for spasm, although it can be technically demanding and does not provide details of the tissue level perfusion. Lewis et al1 36 suggest, however, that these techniques provide complementary examinations in that there may not be a SPECT abnormality concordant with a documented high flow state on Doppler sonography when there is maintained autoregulation. Davis et al40 found SPECT to be of value when evaluating patients for vasospasm and in whom the presence and severity of the neurologic deficits correlated with the regional hypoperfusion. There may be a conceptual case against using Tc-99m HMPAO to study the question of stroke-related vasospasm as the presence of luxury perfusion may underrepresent the ischemic damage. Also, Hellman and Tikofsky 79 suggested that imaging with Tc-99m HMPAO should be delayed for 3 or 4 hours post injection to allow sufficient time for the blood background, which may be elevated in the presence of vasospasm because of increased CBV. SPECT is often used in complicated or confusing cases to decide on the presence or absence of spasm. One valuable aid in evaluating the significance of flow disturbances is a prior or baseline scan; alternatively serial studies also would allow greater confidence in predicting the likelihood for spasm. Brain Death

The diagnosis of brain death can be extremely challenging especially when there are confounding medical and pharmacologic problems. Definite criteria have been established to aid in the diagnosis; one of these is the use of the cerebral radionuclide angiogram. In the past, this has been performed with tracers such as Tc-99m DTPA. With the advent of the newer brain perfusion tracers, however, it is possible to obtain the angiogram component

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and also to acquire the delayed image of brain uptake, which in most cases is an all-ornothing phenomenon. The presence of focal tracer uptake anywhere in the brain indicates persisting brain blood flow and the absence of uptake is indicative of brain death. Having the image of delayed uptake in addition to the angioscintigraphy phase may circumvent technical inadequacies with the angiogram phase, such as jugular reflux or venous sinus activity. It is important to obtain lateral views in addition to the anterior images as this allows optimal imaging of the posterior circulation territory. 192 SPECT images of the brain are likely to be more sensitive in depicting minor areas of tracer uptake that may be called negative on planar images but the clinical significance of such areas is questionable. The ability to perform SPECT on these patients is logistically difficult, and most reports of this technique are of planar acquisitions. Direct comparison of Tc99m DTPA and Tc99m HMPAO have yielded similar results in the flow evaluation, and the delayed HMPAO images were also concordant. 193 The examination may be performed by a mobile camera if available and should include immediate dynamic and static images. Figure 12 represents an example of a brain death study that shows no delayed uptake and is contrasted with the normal appearance of a planar brain study. Arteriovenous Malformations

A VMs may present as intracerebral or intraventricular hemorrhage (which can be fatal), as seizures, or as a steal phenomenon caused by the large blood flow through the malformation. Xe-133 brain SPECT has shown a significant incidence of steal, and this has provided some indications for surgery. 13• 14• 93 In general, on perfusion imaging, the site of a significant cerebral A VM will appear as an area of reduced or absent uptake as there are no parenchymal brain cells to extract the perfusion tracer. This contrasts with Xe-133 SPECT images where it appears as an area of high flow .86 Brain SPECT may be of value for patients with AVMs in the following situations: firstly, documenting the presence of steal/ischemia in the surrounding brain, which may provide a rationale for surgery. Secondly, others have used acetazolamide to evaluate the risk for patients with AVMs, showing that abnormally en-

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Brain Death

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Figure 12. Planar Tc-99m HMPAO brain perfusion image showing example of brain death and contrasting normal planar image. Top row shows anterior and right lateral views, with no uptake in the brain parenchyma; the bottom row are the corresponding views in a normal patient.

hanced vasoreactivity in areas of depressed CBF on the baseline study has worse outcome as a group. 12 Carotid Occlusion Studies

Occlusion or sacrifice of the internal carotid artery is considered in the management of aneurysms of the internal carotid artery and extensive tumors of the head and neck and base of the skull. Assessment of the collateral circulation via the circle of Willis is critical to the success of these operations. This can be achieved with a trial balloon occlusion of the offending artery, noting symptoms of ischemia. There is a subset of patients (5%-20%) that appears to tolerate occlusion only to undergo a cerebral infarct following sacrifice of the artery. 42, 71 The SPECT carotid artery occlusion study consists of a temporary balloon ca-

rotid occlusion in the angiography suite, which is terminated if the patient develops clinical signs. After approximately 15 minutes of asymptomatic occlusion, the patient is injected with the brain perfusion tracer to be scanned later following withdrawal of the balloon and catheter. It should be emphasized that some form of quantitation aids in the interpretation, giving left/right ratios, which can be compared to a baseline study if required. Dementia

Alzheimer's Disease

Brain SPECT studies have gained increasing acceptance in the evaluation of dementia and related conditions. 39 Dementia of the Alzheimer's type (DAT), which accounts for 50% of all dementia, is a progressive degenerative

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brain disorder of slow onset characterized by neuronal loss with neurofibrillary tangles and plaques in cortical brain tissue. It is most pronounced in the medial temporal lobes, the hippocampus, the posterior parietal lobes, and in the later course the frontal lobes. Classification can be made on clinical criteria but this can be unreliable and may be complicated by other medical diseases such as depression. The accuracy of clinical in vivo diagnosis is quoted to be 80% with one in five false positives. 157 Workup based on a diagnosis of exclusion usually includes history and physical examination with neuropsychiatric/neurophysiologic testing as well as anatomic imaging with either CT or MR imaging. The latter is used to exclude a structural lesion that could produce secondary dementia, or to indicate multi-infarct or vascular dementia. Although there are some anatomic imaging features that may indicate dementia such as high signal intensity in the periventricular, deep, and subcortical white matter on T2-weighted images, as well as hippocampal atrophy and selective dilatation of the third ventricle, these are not specific for DAT and have been observed in the aged without dementia.16' 62' 180 Early on in the disease course patients generally present with mild memory, personality, or cognitive defects. PET brain imaging has characterized decreased metabolism in the temporal and parietal lobes and has been able to differentiate patients from controls with a high degree of accuracy. 49, 77, 78, 83 Brain perfusion SPECT findings in DAT have been similar to the PET observations with bilateral temporal and posterior parietal perfusion reduction. 46, 61 , 3o, 91 , 100 There remains concern, however, over the specificity of these findings as similar features have been observed in Parkinson's disease, depression, cerebrovascular disease, hypoglycemia, carbon monoxide poisoning, Huntington's disease, and CreutzfeldtJakob disease. 73' 122' 129' 154 It is possible that SPECT is not as sensitive for mild or early DAT as compared with PET but this may just reflect the difference in resolution between PET and SPECT and the lack of absolute quantitation with SPECT. 121 Also, it is questionable whether this is clinically relevant. Figure 13 is an example of the typical appearance of DAT. In DAT, perfusion usually persists in the occipital and motor-sensory cortices, the basal ganglia, frontal regions, and the cerebellum. In severe cases there can be involvement of the frontal and to a lesser extent the occipital

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lobes. Bonte et al,24 using Tc-99m HMPAO, showed a sensitivity of 85% and specificity of 64% for diagnosing DAT.24 Although symmetrical perfusion reduction in the posterior temporal-parietal cortices has the strongest predictive power for DAT, correct in 84% of cases, it should be noted that asymmetrical changes are also not uncommonly observed. 43, 91 Although there is some overlap with other disease entities, as mentioned previously, there is evidence of the clinical utility for SPECT in separating Alzheimer's disease patients from controls. 104' 168 Holman et al 91 showed that with the combination of memory loss symptoms and typical perfusion defects, the sensitivity for DAT was 82% compared with 19% for symptoms alone. Unilateral perfusion defects were less sensitive at 57%, and frontal defects had a sensitivity of 43%. The sensitivity of SPECT increases with the severity of the dementia, and in patients with a normal SPECT there is low probability for DAT.104 The evaluation of DAT is complicated by the lack of studies with pathologic follow-up. The Oxford Project to Investigate Memory and Aging (OPTIMA) has accumulated a large series of patients with post-mortem correlation. They found that SPECT alone correctly detected 95% of DAT, with a 12.5% false positive rate. By adding fine-cut head CT scanning to measure the hippocampal thickness the sensitivity dropped slightly to 90% but the false positive rate improved to only 3%. 102, 103 Bonte et al25 reported recently on their SPECT results in 424 patients having pathologic results in 52, and found a sensitivity of 85.3%, specificity of 72.7%, positive predictive value of 92.1 %, and negative predictive value of 57.1%. 25 Brain SPECT perfusion imaging also may have application in the evaluation of treatment options for DAT as was shown by Agnoli et al. 2 A number of studies have evaluated the role of receptor imaging agents in DAT with mixed results.89, 207, 208 Frontal Lobe Dementia

The most common dementia affecting the frontal lobes is Pick's disease, which is associated with cognitive and behavioral changes. Studies with PET and with SPECT have shown frontal and temporal lobe metabolism and perfusion reductions correlating with atrophy observed on CT and MR imaging. 24, 107, 121, 209

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B Figure 13. Tc-99m HMPAO SPECT brain perfusion images showing typical pattern of Alzheimer's disease. A, Transverse images with arrows indicating the reduced perfusion to the posterior parietal lobes. B, Sagittal images with arrow indicating posterior parietal perfusion reduction.

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In general, the characteristic pattern of frontal perfusion reduction with Pick's disease allows separation from the classic pattern of DAT and multi-infarct dementia. 24 • 107• 121 There are a number of other degenerative conditions that have been associated with frontal perfusion changes on SPECT, including progressive supranuclear palsy, normal pressure hydrocephalus, and motor neuron disease.29• 67• 162 Figure 14 is an example of a predominantly frontal lobe dementia.

There are two categories of multi-infarct dementia, one involving predominantly the large vessels and producing large cerebral infarcts and the other producing multiple small, deep, subcortical lacunar and pericapsular infarcts. 86 Typically, the SPECT appearance of multiinfarct dementia can be differentiated from DAT when the usual posterior temporoparietal pattern of DAT is present. 99 • 187 As the end results of vascular dementia often are readily apparent on CT or MR imaging, there may be a role for SPECT in identifying patients at future risk for further ischemic damage or possibly in identifying patients early in the course of the disease. This may be possible with the use of acetazolamide challenge as was postulated by Bonte et al,23 in which the patients with DAT showed improved temporoparietal perfusion and those with vascular compromise showed the same or decreased rCBF.

Vascular Dementia

Vascular dementia is the most common dementia following DAT, and is composed of a number of different entities such as Binswanger' s disease, which involves the microcirculation (atherosclerosis of the penetrating arteries) and presents as white matter disease.

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Figure 14. Tc-99m HMPAO SPECT brain perfusion sagittal images showing the typical pattern of Pick's disease with bifrontal perfusion reduction.

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AiDS Dementia Compiex

Patients with AIDS suffer from a number of neuropsychiatric conditions that may mimic AIDS dementia complex (ADC). Anatomic imaging may identify structural lesions that can cause deteriorating cognitive function. Brain SPECT, however, has been shown to be sensitve for the perfusion changes that are present in ADC and, therefore, could allow prompt anti-HIV treatment.52, 170' 199 The perfusion changes are most commonly patchy cortical and subcortical hypoperfusion predominantly in the frontal, temporal, and parietal lobes. 88 Parkinson's Disease and Other Neurologic Disorders

Dementia can occur in the later stages of Parkinson's disease and often results in perfusion abnormalities that are similar to those found in DAT.121, 154, 189 Other authors, however, have found that there is also reduced perfusion to the frontal lobes in patients with Parkinson's disease. 179, 188 It is reasonable to include Parkinson's disease in the differential diagnosis of posterior temporoparietal perfusion abnormalities, but clinically pre-existing symptoms and signs should allow the separation of these two conditions. Basal ganglia perfusion patterns in Parkinson's disease have been conflicting, and the use of dopamine transporter agents are likely to be more promising.32, 157, 183 Huntington's chorea also is associated with dementia but is not discussed. 154 There are a number of miscellaneous neurologic conditions that may or may not be associated with dementia. Primary progressive aphasia is associated with predominantly left temporal hypoperfusion with similar abnormalities being observed on PET imaging.132, 158 As DAT is often associated with disordered language, brain perfusion SPECT may be useful in separating patients with primary progressive aphasia from DAT. Figure 15 is an example of a patient with primary progressive aphasia. Head Injury

Head injury is a significant consumer of medical and financial resources, particularly if there is subsequent physical or neuropsychological disability. Anatomic imaging with CT or MR imaging will show significant structural

abnormalities but is generally unrewarding in cases of mild head trauma. This contrasts with neuropsychological testing, which may show abnormalities for several months following mild head trauma evaluated with normal conventional imaging.68, 108, 159, 195, 196 Therefore, some authors have suggested the addition of other imaging criteria for the diagnosis of mild head trauma.177' 211 Brain perfusion SPECT has been shown to be more sensitive than CT in detecting abnormalities following minor trauma, a 50% increase over CT in one study. In addition, SPECT was able to demonstrate abnormalities in 10 of 14 patients who had normal CT scans following mild trauma. 72' 142 Additionally, it seems that the changes on the perfusion SPECT occur earlier than on CT and that the extent of the abnormalities appears to mirror the severity of the post-traumatic syndrome.51, 93, 172 The clinical significance of these findings, however, is uncertain but the study may have a role in establishing credibility to posttraumatic neuropsychological complaints in a select group of patients. 61 ' 72 There also may be a role in predicting the outcome of patients in persistent post-traumatic vegetative state. 197 The Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of N eurology suggests that the routine use of brain perfusion SPECT be investigated in head injury.6

Brain Neoplasms

The diagnosis of brain malignancy, which generally carries a grave prognosis, is well served by structural imaging with CT and MR imaging. With newer and more effective forms of therapy, however, patients now live longer and require assessment for recurrent tumor. 139 Unfortunately, with both CT and MR imaging, it is difficult to distinguish radiation necrosis from recurrent tumor. 48, 205 A number of radiopharmaceuticals localize in tumors (e.g., thallium-201 [Tl-201], gallium-67, Tc-99m sestamibi, and F-18 fluoro-deoxyglucose [FOG]). A PET facility, however, is required for the FOG, and gallium has not met with much success in the evaluation of brain neoplasms. Of the two remaining agents, Tl-201 has been studied the most. Both Tl-201 and Tc-99m sestamibi have had extensive use in the evaluation of myocardial perfusion as flow dependenttracers. Tl-210 localizes in tumors according to blood flow. In

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Figure 15. Tc-99m ECO SPECT brain perfusion image (top panel is transverse images; bottom panel is coronal images) showing reduced left temporal lobe uptake (arrow) in a patient with progressive aphasia.

addition, it uses an Na/K dependent ATPase mechanism, giving indication of tumor vascularity and the metabolic activity. This is slightly different from Tc-99m sestamibi which following vascular delivery, is localized according to the cellular membrane potential gradients, with final localization in the mitochondria. Tl201 uptake into brain tumors appears to reflect the malignant potential of the cells, with the most malignant tumors exhibiting greatest uptake.20· 97· 111 This may be of value in determining

the site for performing a biopsy of heterogeneous tumor masses. Co-registration computer programs, such as ANALYZE (Biomedical Imaging Resource, Mayo Foundation, Rochester, MN), are available to superimpose SPECT data over CT or MR imaging data facilitating accurate localization of abnormal uptake. Combining Tl-201 and Tc-99m HMPAO in the evaluation of tumor recurrence versus radiation necrosis brain tumors shows three patterns of activity: firstly, marked thallium uptake is

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highly predictive of tumor recurrence; the association of low thallium and Tc-99m HMPAO uptake indicates a low likelihood for tumor recurrence; and finally, moderate thallium uptake in the setting of increased local perfusion is indeterminate for recurrence. 182 Figure 16 is an example of high thallium uptake in a recurrent brain tumor. Kahn et showed106 that Tl-201 was as accurate as F-18 FDG PET in determining the presence of recurrent brain tumor, and Kosuda et al113 demonstrated that quantitative Tl-201 SPECT was able to predict survival of patients with suspected tumor recurrence. Thallium also has demonstrated ability to differentiate the presence of cerebral lymphoma in AIDS patients when the differential was such nonmalignant conditions as toxoplasmosis.176 Al-

though false positives are rare, one documented case of thallium uptake in an abscess has been reported as well as one in radiation necrosis. 114• 150 The introduction of Tc-99m sestamibi for myocardial imaging and demonstration of activity in parathyroid and breast tumors has fostered its use for the evaluation of brain tumor recurrence. 36• 110 There are technical advantages for Tc-99m sestamibi use, namely that it can be used in significantly higher doses because of its more favorable physical characteristics, which translates into apparently better tumor-to-background ratios, thus giving better edge delineation to tumor uptake. It does, however, demonstrate quite intense choroid plexus and, to a lesser extent pituitary gland uptake, which can limit its usefulness

Figure 16. SPECT brain Tl-201 transverse images (top row) and T-2 MR imaging axial scan (bottom image). Thallium-201 uptake at the site of tumor recurrence (black arrow). The MR image shows increased T-2 signal in the posterior right parietal lobe with a small circumscribed area of slightly less increases signal (adjacent to white arrow) that corresponds to the area of thallium uptake at the site of tumor recurrence.

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in the deeper-seated tumors. There is also scalp and salivary gland activity. This occurs despite treatment with potassium perchlorate.7· 161 Figure 17 is an example of the use of sestamibi in the imaging of a recurrent brain tumor.

Epilepsy

Epilepsy represents a significant problem that afflicts approximately 1.5 million people in the United States. Although treatment has been refined, some patients who remain poorly controlled or refractory to treatment may require surgical intervention to control their seizures, particularly those with complex partial seizures. Successful surgery most often is limited to the temporal or frontal lobes and requires accurate preoperative localization. The noninvasive preoperative assessment of these patients generally includes scalp electroencephalogram (EEG), video EEG monitoring of interictal and ictal activity, neuropsychological assessment, socal/ emotional evaluation, and neuroimaging studies. MR imaging, PET, SPECT and possibly CT are the principal imaging studies used. EEG localization of seizure activity is considered the gold standard for surgical intervention but it may require more than scalp electrodes. Invasive techniques such as intraoperative corticography and depth electrode sampling are available but are expensive and have definite risks associated with them. In some neurosurgical centers, patients

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w ith classic temporal lobe seizures (TLE) with a clear-cut surface EEG focus and an obvious abnormality on MR imaging, such as hippocampal sclerosis or temporal lobe atrophy, may not require further invasive evaluation or noninvasive imaging and may be simply taken to surgery after the usual evaluations. Patients with nonlesional seizures, poorly documented EEG foci, or extra temporal sites, however, generally require further evaluation. Functional brain imaging with PET has been used to assess the site of seizure activity, and is characterized by interictal hypometabolism on F-18 FDG studies.58· 116 Most interictal PET temporal lobe studies show mesial temporal hypometabolism. Generally, the extent of the temporal lobe hypometabolism is greater than the structural abnormality and can extend outside the field of interest to basal ganglia, thalamus, and to surrounding cortical structures.57· 81 The sensitivity of interictal PET as determined by scalp and depth interictal and ictal EEG recordings is in the region of 70% 56·145It should be noted that other processes may cause PET glucose hypometabolism such as low-grade gliomas and hamartomas. Because of the equilibrium nature of the FDG uptake there is little possibility of obtaining true ictal images. Interictal brain perfusion SPECT was first performed in 1983with1-123 IMP 201 and unfortunately, has only moderate sensitivity and specificity, less than does PET. Typical figures for TLE range from 30% to 70%.189 This may

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Figure 17. SPECT brain Tc-99m transaxial sestamibi images showing uptake in a brain tumor recurrence posteriorly (solid arrow) and norm al choroid plexus sestam ibi uptake (dashed arrow).

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be due to differing resolutions of the two techniques, differing patient populations, differing outcomes against which the techniques were compared, the side-to-side asymmetry in normal temporal lobes, and lack of documenting the true interictal status of the patient. Additionally, the optimal method of image review (displaying the temporal lobes elongated in an oblique transaxial and coronal view) was not popularized until the advent of ictal imaging. Figure 18 demonstrates the appropriate method of display for transaxial review. Ictal SPECT requires an injection of the tracer at the time of seizure, or closely related to the seizure onset (peri-ictal). This necessitates the localization of radionuclide facilities to the epilepsy monitoring area. Most often this is the inpatient video monitoring area, where simultaneous visual and EEG assessment are possible. Tc-99m ECD and the recently approved stabilized Tc-99m HMPAO have allowed quicker access time following the identification of seizure activity. Ideally, this should be within 40 seconds. A large number of studies have shown that ictus-related injection of radiolabeled tracer in patients w ith epilepsy documents increased cerebral blood flow. 45, 57, 59, 64, 93, 95, 115, 117, 123

Essentially the ictal time period encompasses the seizure duration or 0 to 30 seconds following the cessation of the seizure, the peri-ictal period from 30 seconds to 2 minutes and postictal period beyond this. 17•76• 159• 162• 190•212 This may not suffice for brief partial seizures in which changes can be extremely rapid. For temporal lobe seizures there is a clear pattern of markedly increased temporal lobe ictal blood flow, involving the mesial and often to a greater extent, the anterolateral neocortical structures. 160• 174• 175• 185•194 This is shortly replaced by lateral temporal lobe hypoperfusion, with some persisting mesial temporal lobe hyperperfusion, in the perithrough immediate postictal period. Finally, generalized hypoperfusion is present throughout the entire temporal lobe, which may be greater than in the interictal state and correlates with the presence of postictal EEG slow waves. 173• 174 The time course of perfusion changes was illustrated by Rowe et al,174 and is similar to that later outlined by Duncan et al. 50 Figure 19 depicts the sequence of perfusion changes in temporal lobe seizures. There also may be augmentation of the ipsilateral basal ganglia and thalamus, especially if there is dystonic posturing.162 Often, the contralateral cerebellum also is increased in what amounts

Figure 18. Tc-99m ECD SPECT brain perfusion images (the top row shows two sagittal slices with orientation marker shown as line). A, The correct temporal slice reconstruction; B, The traditional transaxial or transverse orientation).

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Figure 19. Time sequence of perfusion changes associated with a typical temporal lobe seizure.

to a diaschisis effect. These structures act as pointers to the side of the seizure if there is some ambiguity from the cortical perfusion pattern, although they cannot be viewed in isolation. Figure 20 demonstrates a typical ictal Tc99m ECO SPECT study in a patient with an abnormal MR image. Figure 21 documents the pattern of perfusion in a peri-ictal study, in which the patient was injected at 80 seconds following the termination of seizure activity. Persisting mesial temporal hyperperfusion is present in the left temporal lobe, with lateral neocortex hypoperfusion, whereas the interictal images show left temporal lobe hypoperfusion. Although the reoriented transaxial and coronal images generally are considered the most informative, the mid to lateral sagittal images are often valuable as a clear comparison can be made between uptake in the temporal and frontal lobes, ictally and interictally. Interpretation of ictal SPECT imaging requires knowledge of the seizure onset/ offset time and relationship to time of injection, the

presence or absence of focal motor activity, generalization of seizure, and whether the seizures are thought to be of temporal or extratemporal origin. The images should be reviewed with appropriate gray scale and, if desired, color scale. If possible, the combination of ictal-interictal scans are the most helpful in the challenging cases. The normalization of the studies is important; currently the author uses a program designed for cardiac interpretation which normalizes each study (ictal or interictal) separately with its maximum determined by the hottest pixel in the group of images. There are more involved methods of analysis that include subtraction of the images after normalization and the production of a difference image that can be reoriented to the MR image or CT scan. Again this is possible with such programs as Analyze. Recent work in our laboratory has suggested that this technique of co-registering a difference image to the MR image may add significantly to the localizing power of the SPECT studies and

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Figure 20. Tc-99m ECO SPECT brain ictal (left) and interictal (right) perfusion images (top row, temporal slices and bottom row, coronal slices) showing markedly increased right temporal lobe blood flow and increase in the right thalamus indicated by the arrow. There is some ictal reduction in the right parietal perfusion.

Figure 21. Tc-99m ECO SPECT brain ictal (A) and interictal (B) perfusion images, temporal slices, showing modestly increased temporal blood flow particularly in the mesial and anterior aspects with interictal hypoperfusion.

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could provide a guide for surgical removal of the ictal focus . Patients in whom the hyperperfusion focus of MR imaging co-registered ictal-interictal subtraction was completely removed had a better seizure-free result than did those in whom the focus was partially excised and better again than those in whom the focus was not excised at all (T O'Brien, personal communication, 1996). The role of ictal SPECT in temporal lobe seizures generally is considered well established; however, there probably is an even greater need for seizure localization in extratemporal seizures. Evaluation of frontal lobe, 123• 131• 194 parietal lobe,84 and occipital lobe 15 seizures is reported in additional studies. Ictal SPECT has improved sensitivity over interictal PET, 91 % versus 83% with similar specificity of 94 %. Ictal SPECT was easier to interpret, had high positive predictive value, and fewer equivocal studies. 18 Receptor imaging may provide an alternative to perfusion and metabolism imaging with PET and SPECT and, as such, mirror the underlying chemical factors that control CBF and metabolism. Work with the benzodiazepine receptor agent I-123 Iomazenil and the muscarinic acetylcholine receptor agent I-123 Dexetimide is progressing but the role of these agents in the routine presurgical evaluation of epilepsy is uncertain. As can be seen, SPECT (primarily ictal) can contribute to the evaluation of patients with partial seizures, specifically TLE with sensitivities approaching 100%. Harvey and Berkovic76 summarized the contribution of SPECT. They suggested that SPECT can (1) confirm the localization of well-documented seizures, (2) suggest or localize nonlocalized partial seizures, and (3) clarify the localization of seizures for which multiple sites are possible or discordant results are present. The number of preoperative invasive monitoring studies performed for TLE at one institution has been reduced because of SPECT.17 The exact mix of SPECT with MR imaging has yet to be determined: Should ictal SPECT be reserved for MR imaging negative cases or when conflict exists with the EEG? Larger studies are required preferably with ictal SPECT, particularly with interictal subtraction and co-registration. SPECT also holds promise in the evaluation of extratemporal seizures for which, with new surgical options, comes the need for precise seizure localization.

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SPECT brain perfusion imaging has definite value in the evaluation of cerebrovascular disease (particularly acute stroke), dementia, epilepsy, and may have a role in the diagnosis of brain death and head trauma. SPECT with tumor tracers Tl-201 and Tc-99m sestamibi shows promise for detecting tumor recurrence.

References l. Ackerman LV, DICOM: The answer for establishing

2.

3. 4. 5. 6.

7. 8. 9.

10. 11. 12.

13.

14.

15.

a digital radiology department [editorial]. Radiographies 14:151, 1994 Agnoli A, Fabbrini G, Fioravanti M, et al: CBF and cognitive evaluation of Alzheimer's type patients before and after IMAO-B treatment: A pilot study. Eur Neuropsychopharmacol 2:31, 1992 Alberts MJ, Faulstich ME, Gray L: Stroke with negative brain magnetic resonance imaging. Stroke 23: 663, 1992 Andersson JL, Sundin A, Valind S: A method for coregistration of PET and MR brain images. J Nucl Med 36:1307, 1995 Anger HO: A New Instrument for Mapping GammaRay Emitters. Washington, Biology and Medicine Quarterly Report UCRL-3653, 1957 Anonymous: Assessment of brain SPECT: Report of the therapeutic and technology assessment subcommittee of the American Academy of Neurology. Neurology 46:278, 1996 Bagni B, Pinna L, Tamarozzi R, et al: SPECT imaging of intracranial tumours with 99Tc-m sestamibi. Nucl Med Commun 16:258, 1996 Baird AE, Donna GA, Saling M: Mechanisms and clinical features of internal watershed infarction. Clin Exp Neural 28:50, 1991 Baird AE, Donnan GA, Austin MC, et al: Reperfusion after thrombolytic therapy in ischemic stroke measured by single-photon emission computed tomography. Stroke 25:79, 1994 Baker JGI, Heras RC: Clinical aspects of vasospasm. Neurosurg Clin North Am 1:277, 1990 Ballinger JR, Reid RH, Gluenchyn KY: Technetium99m HM-PAO stereoisomers: Differences in interaction with glutathione. J Nucl Med 29:1998, 1988 Batjer HH, Devous MOS: The use of acetazolamideenhanced regional cerebral blood flow measurement to predict risk to arteriovenous malformation patients. Neurosurgery 31:213, 1992 Batjer HH, Devous MOS, Meyer YJ: Cerebrovascular hemodynamics in arteriovenous malformation complicated by normal perfusion pressure breakthrough. Neurosurgery 22:503, 1988 Batjer HH, Devous MOS, Siebert GB, et al: Intracranial arteriovenous malformation: Relationships between clinical and radiographic factors and ipsilateral steal severity. Neurosurgery 23:322, 1988 Bauer J, Schuler P, Feistel H, et al: Blindness as an ictal phenomenon: Investigations with EEG and SPECT in two patients suffering from epilepsy. J Neural 238:44, 1991

646

MULLAN et al

16. Bennett DA, Gilley DW, Wilson RS, et al: Clinical correlates of high signal lesions on magnetic resonance imaging in Alzheimer's disease. J Neural 239:186, 1992 17. Berkovic SF, Newton MR, Rowe CC: Localization of epileptic foci using SPECT. In Luders H (ed): Epilepsy Surgery. New York, Raven Press, 1991, p 251 18. Berlangieri SU, Ho SS, Newton MR, et al: Interictal F-18 FDG PET and Tc-99m HMPAO ictal SPECT for seizure focus localization in patients with refractory temporal lobe epilepsy [abstract]. Eur J Nucl Med 2l:S43, 1994 19. Bidgood WDJ, Horii SC: Introduction to the ACRNEMA DICOM standard. Radiographies 12:345, 1992 20. Black KL, Hawkins RA, Kim KT, et al: Use of thallium-201 SPECT to quantitate malignancy grade of gliomas. J Neurosurg 71:342, 1989 21. Bogousslavsky J, Regli F: Borderzone infarctions distal to internal carotid artery disease. Ann Neural 20:346, 1986 22. Bogousslavsky J, Delaloye-Bischof A, Regli F, et al: Prolonged hypoperfusion and early stroke after transient ischemic attack. Stroke 21:40, 1990 23. Bonte FJ, Devous MDS, Reisch JS, et al: The effect of acetazolamide on regional cerebral blood flow in patients with Alzheimer's disease or stroke as measured by single-photon emission computed tomography. Invest Radio! 24:99, 1989 24. Bonte FJ, Horn J, Tintner R, et al: Single photon tomography in Alzheimer's disease and the dementias. Semin Nucl Med 20:342, 1990 25. Bonte FJ, Weiner MF, Bigio E, et al: Brain blood flow in the dementias: SPECT with histopathologic correlation. J Nucl Med 37:79P, 1996 26. Bose A, Pacia SB, Fayad P, et al: Cerebral blood flow imaging compared to CT during the inital 24 hours of cerebral infarction. Neurology 40:190, 1990 27. Brass LM, Walovitch RC: Two prospective, blinded, controlled trials of Tc-99m bicisate brain SPECT and standard neurological evaluation for identifying and localizing ischemic strokes. Journal of Stroke and Cerebrovascular Diseases 1:559, 1992 28. Brass LM, Walovitch RC, Joseph JL, et al: The role of single photon emission computed tomography brain imaging with 99mTc-bicisate in the localization and definition of mechanism of ischemic stroke. J Cereb Blood Flow Metab 14(suppl l:S91, 1994 29. BrownJ: Pick's disease. Bailliere's Clinical Neurology 1:535, 1992 30. Brunetti A, Soricelli A, Rotondo A, et al: Correlative morphologic and functional imaging for d iagnosis, staging and follow up in AIDS: An overview. Quarterly Journal of Nuclear Medicine 39:201, 1995 31. Budde P, Hung JC, Mahone DW, et al: Rapid quality control procedure for technetium-99m-bicisate. Journal of Nuclear Medicine and Technology 23:190, 1995 32. Carroll FI, Scheffel U, Dannals RF, et al: Development of imaging agents for the dopamine transporter [review]. Med Res Rev 15:419-444, 1995 33. Castagnoli A, Borsato N, Bruno A, et al: SPECT brain imaging in chronic stroke and dementia: A comparison of 99mTc-ECD and 99mTc-HMPAO. In Hartmann A, Kuschinsky W, Hoyer S (eds): Cerebral Ischemia and Dementia. Berlin and New York, SpringerVerlag, 1991, p 327

34. Choksey MS, Costa DC, Iannotti F, et al: 99mTcHMPAO SPECT and cerebral blood flow : A study of CO, reactivity. N ucl Med Commun 10:609, 1989 35. Chollet F, Celsis P, Clanet M, et al: SPECT study of cerebral blood flow reactivity after acetazolamide in patients with transient ischemic attacks. Stroke 20:458, 1989 36. Coakley AJ, Kettle AG, Wells CP, et al: 99Tcm sestamibi-a new agent for parathyroid imaging. Nucl Med Commun 10:791, 1989 37. Crow W, Guinto FCJ: Limitations of CT in the evaluation of transient ischemic attacks. Tex Med 78:65, 1982 38. Datz FL: Central nervous system imaging. In Datz FL (ed): Handbook of Nuclear Medicine. St. Louis, Mosby, 1993, p 35 39. Davis K: The scintigraphic appearance of Alzheimer's disease: A prospective study using technetium-99mHM-PAO SPECT [editorial]. J Nucl Med 33:312, 1992 40. Davis SM, Andrews JT, Lichenstein M, et al: Correlations between cerebral arterial velocities, blood flow, and delayed ischemia after subarachnoid hemorrhage. Stroke 23:492, 1992 41. De Roo M, Mortelmans L, Devos P, et al: Clinical experience with Tc-99m HM-PAO high resolution SPECT of the brain in patients with cerebrovascular accidents. Eur J Nucl Med 15:9, 1989 42. de Vries EJ, Sekhar LN, Horton JA, et al: A new method to predict safe resection of the internal carotid artery. Laryngoscope 100:85, 1990 43. Derousesne C, Rancurel G, Le Poncin M, et al: Variability of cerebral blood flow defects in Alzheimer's disease on 123-iodo-isopropyl-amphetamine and single-photon emission tomography [letter]. Lancet 1:1282, 1985 44. Devous MD: SPECT functional brain imaging: Technical considerations. J Neuroimaging 5:S2, 1995 45. Devous MD, Leroy RF, Homan RW: Single photon emission computed tomography in epilepsy. Semin Nucl Med 20:325, 1990 46. Devous MD: Comparison of SPECT applications in neurology and psychiatry. J Clin Psych 53:13, 1992 47. Devous MDS, Batjer HH, Ajmani AK, et al: SPECT measurements of cerebrovascular reserve in patients with hemodynamic risk. J N ucl Med 29:911, 1988 48. Dooms GC, Hecht S, Brant-Zawadzki M, et al: Brain radiation lesions: MR imaging. Radiology 158:149, 1986 49. Duara R, Barker WW, Chang J, et al: Viability of neocortical function shown in behavioral activation state PET studies in Alzheimer's disease. J Cereb Blood Flow Metab 12:927, 1992 50. Duncan R, Patterson J, Roberts R, et al: Ictal/ postictal SPECT in the pre-surgical localisation of complex partial seizures. J Neural Neurosurg Psych iatry 56:141, 1993 51. Echise M, Chung DG, Wang P, et al: Technetium99m-HMPAO SPECT, CT and MRI in the evaluation of patients with chronic traumatic brain injury: A correlation with neuropsychological perform ance. J Nucl Med 35:217, 1991 52. Ell PJ, Costa DC, Harrison M: Imaging cerebral damage in HIV infection. Lancet 2:569, 1987 53. Ell PJ, Hocknell JML, Harritt PH, et al: A Tc-99mlabeled radiotracer for the investigation of cerebral vascular disease. N ucl Med Commun 6:437, 1985

SINGLE PHOTON EMISSION COMPUTED TOMOGRAPHY BRAIN IMAGING

54. Ell PJ, Jarritt PH, Costa DC, et al: Functional imaging of the brain. Semin Nucl Med 17:214, 1987 55. Ell PJ, Jarritt PH, Cullum I, et al: Regular cerebral blood flow mapping with 99mTc-labelled compound [letter]. Lancet 2:50, 1985 56. Engel J Jr: The use of positron emission tomographic sca1ming in epilepsy. Ann Neural 15(suppl):S180Sl91, 1994 57. Engel J Jr, Brown WJ, Kuhl DE, et al: Pathological findings underlying focal temporal lobe hypometabolism in partial epilepsy. Ann Neural 12:518, 1982 58. Engel J Jr, Kuhl DE, Phelps ME, et al: Interictal cerebral glucose metabolism in partial epilepsy and its relation to EEG changes. Ann Neural 12:510, 1982 59. Engel JPJ, Babb TL, Phelps ME: Contribution of positron emission tomography to understanding mechanisms of epilepsy. In Engel JJ, Ojemann G, Luders H, Williamson P (eds): Fundamental Mechanisms of Human Brain Function. New York, Raven Press, 1987, p 209 60. English RJ, Holman BL: Current status of cerebral perfusion radiopharmaceuticals. Journal of Nuclear Medicine and Technology 15:30, 1987 61. Farkas T, Ferris SH, Wolf AP, et al: 18F-2-deoxy-2fluoro-D-glucose as a tracer in the positron emission tomographic study of senile dementia. AmJ Psychiatry 139:352, 1982 62. Faulstich ME: Brain imaging in dementia of the Alzheimer type. Int J Neurosci 57:39, 1991 63. Fayad PB, Brass LM: Single photon emission computed tomography in cerebrovascular disease. Stroke 22:950, 1991 64. Fersti F, Cordes M, Cordes I: 123-I-iomazenil-SPECT in patients with focal epilepsies-A comparative study with Tc-99m HMPAO-SPECT, CT and MR. Presented at the International Symposium on Neurotransmitter Receptors (ed 3), Hiroshima, Japan, 1990 65. Fieschi C, Argentina C, Lenzi GL, et al: Clinical and instrumental evaluation of patients with ischemic strokes within the first six hours. J Neural Psychiatry 91:311, 1989 66. Foulkes MA, Wolf PA, Price TR, et al: The Stroke Data Bank: Design, methods and baseline characteristics. Stroke 19:547, 1988 67. Gastafson L, Brun A, Passant U: Frontal lobe degeneration of non-Alzheimer's type. Bailliere's Clinical Neurology. 1:559, 1992 68. Gentilini M, Nichelli P, Schoenhuber R: Assessment of attention in mild head injury. In Eisenberg HM, Levin HS, Benton AL (eds): Mild Head Injury. New York, Oxford University Press, 1989, p 163 69. Gibbons RJ, Christian TF, Hopfenspirger M, et al: Myocardium at risk and infarct size after thrombolytic therapy for acute myocardial infarction: Implications for the design of randomized trials of acute intervention. J Am Coll Cardiol 24:616, 1994 70. Giubilel F, Lenzi GL, Di Fiero V, et al: Predictive value of brain perfusion single-photon emission computed tomography in acute ischemic stroke. Stroke 21: 895, 1990 71. Gonzalez CF, Moret J: Balloon occlusion of the carotid artery prior to surgery for neck tumors. AJNR Am J Neuroradiol 11:649, 1990 72. Gray BG, Ichise M, Chung DG, et al: Technetium99m-HMPAO SPECT in the evaluation of patients with a remote history of traumatic brain injury: A

647

comparison with x-ray computed tomography . J Nucl Med 33:52, 1992 73. Habert MO, Spampinato U, Mas JL, et al: A comp arative technetium 99m hexamethylpropylene amine oxime SPECT study in different types of dementia. Eur J Nucl Med 18:3, 1991 74. Hanson SK, Grotta JC, Rhoades H, et al: Value of single-photon emission-computed tomography in acute stroke therapeutic trials. Stroke 24:1322, 1993 75. Hartmann A: Prolonged disturbance of regional cerebral blood flow in transient ischemic attacks. Stroke 16:932, 1985 76. Harvey AS, Berkovic SF: Functional neuroimaging with SPECT in children with partial epilepsy. Child Neural 9(suppl l):S71-S81, 1994 77. Haxby JV, Duara R, Grady C, et al: Relations between neuropsychological and cerebral metabolic asymmetries in early Alzheimer's disease. J Cereb Blood Flow Metab 5:193, 1985 78. Haxby JV, Grady CL, Duara R, et al: Neocortical metabolic abnormalities precede nonmemory cognitive defects in early Alzheimer's type dementia. Arch Neural 43:882, 1986 79. Hellman RS, Tikofsky RS: An overview of the contribution of regional cerebral blood flow studies in cerebrovascular disease: Is there a role for single photon emission computed tomography? Semin N ucl Med 20:303, 1990 80. Hellman RS, Tikofsky RS, Van Heertum R, et al: A multi-institutional study of interobserver agreement in the evaluation of dementia with rCBF / SPET technetium-99m exametazime (HMPAO). Eur J Nucl Med 21:306, 1994 81. Henry TR, Mazziotta JC, Engel J Jr: Interictal metabolic anatomy of mesial temporal lobe epilepsy. Arch Neural 50:582, 1993 82. Herderschee D, Limburg M, van Royen EA, et al: Thrombolysis with recombinant tissue plasmin ogen activator in acute ischemic stroke: Evaluation with rCBF-SPECT. Acta Neural Scand 85:3317, 1991 83. Herholz K: FOG PET and differential diagnosis of dementia. Alzheimer Dis Assoc Disord 9:6, 1995 84. Ho SS, Berkovic SF, Newton MR, et al: Parietal lobe epilepsy: Clinical features and seizure localization by ictal SPECT. Neurology 44:2277, 1994 85. Hoffman TJ, Corliga M, Chaplin SB, et al: Retention of [99mTc]-d,I-HM-PAO in rat brain: An autoradiographic study. J Cereb Blood Flow Metab 8:S38, 1988 86. Holman BL, Devous MD Sr: Functional brain SPECT: The emergence of a powerful clinical method. J Nucl Med 33:1888, 1992 87. Holman BL, Carvalho PA, Zimmerman RE, et al: Brain perfusion SPECT using an annular single crystal camera: Initial clinical experience. J Nucl Med 31:1456, 1990 88. Holman BL, Garada B, Johnson KA, et al: A comparison of brain perfusion SPECT in cocaine abuse and in AIDS dementia complex. J Nucl Med 33:1312, 1992 89. Holman BL, Gibson RE, Hill TC, et al: Muscarinic acetylcholine receptors in Alzheimer's disease: in vivo imaging with iodine-123 labelled 3quinuclidinyl-4-lodobenzilate and emission tomography. JAMA 254:3063, 1985 90. Holman BL, Hellman RS, Goldsmith SJ, et al: Biodistribution, dosimetry and clinical evaluation of technetium-99m ethyl cysteinate dimer in normal

648

91.

92. 93.

94.

95. 96.

97.

98.

99. 100.

101.

102.

103.

104.

105.

106.

107.

MULLAN et al

subjects and in patients w ith chronic cerebral infarction. J Nucl Med 30:1018, 1989 Holman BL, Johnson KA, Gerada B, et al: The scintigraphic appearance of Alzheimer's disease: A prospective study using technetium-99m HMPAO SPECT. J Nucl Med 33:181, 1992 Homan RW, Devous MDS, Stokely EM, et al: Quantification of intracerebral steal in p atients with arteriovenous malformation. Arch Neurol 43:779, 1986 Homan RW, Paulman RG, Devous MD Sr, et al: Cognitive function and regional cerebral blood flow in partial seizures. Arch Neurol 46:964, 1989 Hung JC, Chowdhury S, Redfern M, et al: Rapid preparation m ethod for technetium-99m-bicisate. J Nucl Med 37:142P, 1996 Ingvar DH: Regional cerebral blood flow in focal cortical epilepsy. Stroke 4:359, 1973 Ingvar DH, Risberg J: Increase of regional cerebral blood flow during mental effort in normals and in patients with focal brain disorders. Exp Brain Res 3:195, 1967 Ishibashi M, Taguchi A, Sugita Y, et al: Thallium201 in brain tumors: Relationship between tumor cell activity in astrocytic tumor and proliferating cell nuclear antigen. J Nucl Med 36:2201, 1995 Jacobs A, Put E, Ingels M, et al: Prospective evaluation of technetium-99m-HMPAO SPECT in mild and moderate traumatic brain injury. J Nucl Med 35:942, 1994 Jagust WJ, Budinger TF, Reed BR: The diagnosis of dementia with single photon emission computed tomography. Arch Neural 44:258, 1987 Jagust WJ, Friedland RP, Budinger TP, et al: Longitudinal studies of regional cerebral metabolism in Alzheimer's disease. Neurology 38:909, 1988 Jaszczak RJ, Floyd CE, Manglos SH, et al: Cone beam collimation for single photon emission computed tomography: Analysis, simulation, and image reconstruction using filtered backprojection. Med Phys 13:484, 1986 Jobst KA, Smith AD, Barker CS, et al: Association of atrophy of the medial temporal lobe w ith reduced blood flow in the posterior parietotemporal cortex in patients with a clinical and pathological diagnosis of Alzheimer's disease. J Neurol Neurosurg Psychiatry 55:190, 1992 Jobst KAO: Alzheimer's disease is accurately diagnosed by combining Tc-99m HMPAO SPECT and temporal lobe oriented x-ray CT scans. J N ucl Med 35:20P, 1994 Johnson KA, H olman BL, Rosen TJ, et al: lofetamine I-123 single photon emission computed tomography is accurate in the diagnosis of Alzheimer's disease. Arch Intern Med 150:752, 1990 Jorgensen HS, Sperling B, Nakayama H, et al: Spontaneous reperfusion of cerebral infarcts in acute stroke patients: Incidence, time course and clinical outcome: The Copenhagen Stroke study . Arch Neural 57: 865, 1994 Kahn D, Follett KA, Bushnell DL, et al: Diagnosis of recurrent brain tumor: Value of 201 Tl SPECT vs 18Ffluorodeoxyglucose PET. AJR Am J Roentgenol 163:1459, 1994 Kamo H, McGreer PL, Harrop R, et al: Positron emission tomography and histopathology in Pick's disease. Neurology 37:439, 1987

108. Kay T, Newman B, Fazzini E: Evidence for brain damage in post-concussion syndrome. Neurology 42:411, 1992 109. Kety SS, Schmidt .CF: The effects of altered arterial tensions of carbon dioxide and oxygen on cerebral blood flow and cerebral oxygen consumption of normal young men. J Clin Invest 27:484, 1948 110. Khalkhali I, Mena I, Jouanne E, et al: Prone scintimammography in p atients with suspicion of carcinoma of the breast. Journal of the American College of Surgeons 178:491, 1994 111. Kim KT, Black KL, Marciano D, et al: Thallium SPECT imaging of brain tumors: Methods and results. J N ucl Med 31:965, 1990 112. Knop J, Thie A, Fuchs C, et al: 99mTc-HMPAOSPECT with acetazolamide challenge to detect hem od ynamic compromise in occlusive cerebrovascular disease. Stroke 23:1733, 1992 113. Kosuda S, Fujii H, Aoki S, et al: Prediction of survival in patients with suspected recurrent cerebral tumors by quantitative thallium-201 single photon emission computed tomography. Int J Radiat Oncol Biol Phys 30:1201, 1994 114. Krishna L, Slizofski WJ, Katsetos CD, et al: Abnormal intracerebral thallium localization in a b acterial brain abscess. J N ucl Med 33:2017, 1992 115. Kuhl DE, Barrco JR, Huang S, et al: Quantifying local cerebral blood flow with N-isopropyl-p-I-123 iodoamphetamine (IMP) tomography. J Nucl Med 23:196, 1982 116. Kuhl DE, Engel J Jr, Phelps ME, et al: Epileptic p atterns of local cerebral metabolism and perfusion in humans determin ed by emission computed tomography of lSFDG and 13NH3. Ann Neural 8:348, 1980 117. Kuikka JT, Mervaala E, Vanninen E, et al: Does technetium-99m bicisate image local brain metabolism in late ictal temporal lobe epilepsy? [see comments]. Eur J Nucl Med 21:1247, 1994 118. Kung HF, Tramposh K, Blau M: A new brain imaging agent: [I-123]HIPDM: N,N,N '-trimethyl-N'-[2hydroxy-3-methyl-5-iodobenzyl]-1,3-propanediamine. J N ucl Med 24:66, 1983 119. Kung HF, Guo YH, Yu C-C, et al: New brain perfusion imaging agents based on 99"'Tc-bis(aminoethanethiol) complexes: Stereoisom ers and biodistribution. J Med Chem 32:437, 1989 120. Kushner M, Alavi A, Relvich M, et al: Contralateral cerebellar hypometabolism follow ing cerebral insult: A positron emission tomographic study. Ann Neural 15:425, 1984 121. Kuwabara Y, Ichiya Y, Otsuka M, et al: Comp arison of I-123 and Tc-99m HMPAO SPECT studies w ith PET in dem entia. Ann Nucl Med 4:75, 1990 122. Kuwabara Y, lchiya Y, Otsuka M, et al: Differential diagnosis of bilateral parietal abnormalities in I-123 IMP SPECT imaging. Clin Nucl Med 15:893, 1990 123. Kuzniecky R, Mountz JM, Wheatley G, et al: Ictal single-photon emission computed tomography demonstrates localized epileptogenesis in cortical dysplasia. Ann Neurol 34:627, 1993 124. Larar GN, Nagel JS: Technetium-99m-HMPAO cerebral perfusion scintigraphy: Considerations for timely brain death declaration. J N ucl Med 33:2209, 1992 125. Lassen NA: Imaging brain infarcts by single-photon emission tomography w ith new tracers. Eur J Nucl Med 21:189, 1994

SINGLE PHOTON EMISSION COMPUTED TOMOGRAPHY BRAIN IMAGING

126. Lassen NA: The luxury perfusion syndrome and its possible relation to acute metabolic acidosis localized within the brain. Lancet 2:1113, 1966 127. Lassen NA, Sperling B: 99mTc-bicisate reliably images CBF in chronic brain diseases but fails to show reflow hyperemia in subacute stroke: Report of a multicenter trial of 105 cases comparing 133Xe and 99mTc-bicisate (ECD, Neurolite) measured by SPECT on same day. J Cereb Blood Flow Metab 14:S44, 1994 128. Lassen NA, Andersen AR, Friberg L, et al: The retention of [99mTc]-d,I-HM-PAO in human brain after intracarotid bolus injection: A kinetic analysis. J Cereb Blood Flow Metab 8:S13, 1988 129. Launes J, Sulkava R, Erkinjuntti T, et al: 99m TcHMPAO SPECT in suspected dementia. Nucl Med Commun 12:757, 1991 130. Laurin NR, Driedger AA, Hurwitz GA, et al: Cerebral perfusion imaging with technetium-99m HM-PAO in brain death and severe central nervous system injury [see comments]. J Nucl Med 30:1627, 1989 131. Lee BI, Markand ON, Wellman HN, et al: HIPDM single photon emission computed tomography brain imaging in partial onset secondarily generalized tonic-clonic seizures. Epilepsia 28:305, 1987 132. Lee H, Kramer JH: Brain SPECT imaging in progressive aphasia. Clin Nucl Med 17:800, 1992 133. Leonard J-P, Nowotnik DP, Neirinckx RD: Technetium-99m-d,I-HM-PAO: A new radiopharmaceutical for imaging regional brain perfusion using SPECT-a comparison with iodine-123 HIPDM. J Nucl Med 27:1819, 1986 134. Leveille J, Demonceau G, Walovitch RC: Intrasubject comparison between technetium-99m-ECD and technetium-99m-HMP AO in healthy human subjects. J Nucl Med 33:480, 1992 135. Leveille J, Demonceau G, DeRoo M, et al: Characterization of technetium-99m-L,L-ECD for brain perfusion imaging, part 2: Biodistribution and brain imaging in humans. J Nucl Med 30:1902, 1989 136. Lewis DH, Eskridge JM, Newell DW, et al: Brain SPECT and the effect of cerebral angioplasty in delayed ischemia due to vasospasm. J Nucl Med 33:1789, 1992 137. Li J, Jaszczak RJ, Turkington TG, et al: An evaluation of lesion detectability with cone-beam, fanbeam and parallel-beam collimation in SPECT by continuous ROC study. J Nucl Med 35:136, 1994 138. Limburg M, van Royen EA, Hijdra A, et al: rCBFSPECT in brain infarction: When does it predict outcome? J Nucl Med 32:382, 1991 139. Loeffler JS, Alexander EI: The role of stereotactic surgery in the management of intracranial tumors. Oncology 4:21, 1990 140. Lucignani G, Rossetti C, Ferrario P, et al: In vivo metabolism and kinetics of [99mTc] HM-PAO. Eur J Nucl Med 16:249, 1990 141. Mallet BL, Veal! N: Measurement of regional cerebral clearance rates in man using xenon-133 inhalation and extracranial recording. Clin Sci 29:179, 1965 142. Masdeu JC, Van Heertum RL, Kleiman A, et al: Early single-photon emission computed tomography in mild head trauma. A controlled study. J Neuroimaging 4:177, 1994 143. Matsuda H, Oba H, Seki H, et al: Determination of flow rate constants in a kinetic model of [99mTc]hexamethyl-propilene amine oxime in the human brain. J Cereb Blood Flow Metab 8:561, 1988

649

144. Matsuda H, Tsuji S, Sumiya H, et al: Acetazolamide effect on vascular response in areas with diaschisis as measured by Tc-99m HMP AO brain SPECT. Clin Nucl Med 17:581, 1992 145. Mazziotta JC, Engel J Jr: The use and impact of positron computed tomography scanning in epilepsy. Epilepsia 25(suppl 2):S86-104, 1984 146. Meneghetti G, Vorstrup S, Mickey B, et al: Crossed cerebellar diaschisis in ischemic stroke: A study of regional cerebral blood flow using 133Xe inhalation and single photon emission computerized tomography. J Cereb Blood Flow Metab 4:235, 1984 147. Messa C, Fazio F, Costa DC, et al: Clinical brain radionuclide imaging studies. Semin Nucl Med 25:111, 1995 148. Miller TD, Christian TF, Hopfenspirger MR, et al: Infarct size after acute myocardial infarction measured by quantitative tomographic 99mTc sestamibi imaging predicts subsequent mortality. Circulation 92:334, 1995 149. Mohanty SK, Thompson W, Rakower S: Are CT scans for head injury patients always necessary? J Trauma 31:801, 1991 150. Moody EB, Hodes JE, Walsh JW, et al: Thallium-avid cerebral radiation necrosis. Clin Nucl Med 19:611, 1994 151. Moore SC, Komis K, Cullum I: Collimator design for single photon emission tomography. Eur J Nucl Med 19:138, 1992 152. Moretti JL, Defer G, Cinotti L, et al: "Luxuryperfusion" with Tc-99m-HMPAO and I-123-IMP SPECT imaging during the subacute phase of stroke. Eur J Nucl Med 16:17, 1990 153. Mountz JM, Model! JG, Foster NL, et al: Prognostiction of recovery following stroke using the comparison of CT and teclmetium-99m HMP AO SPECT. J Nucl Med 31:61, 1990 154. Nagel JS, Ichise M, Holman BL: The scintigraphic evaluation of Huntington's disease and other movement disorders using single photon emission computed tomography perfusion brain scans. Semin Nucl Med 21:11, 1991 155. Nelrinckx RD, Burke JF, Harrison RC, et al: The retention mechanism of technetium-99m-Hm-PAO: Intracellular reaction with glutathione. J Cereb Blood Flow Metab 8:54, 1988 156. Nelrinckx RD, Canning LR, Piper IM, et al: Technetium-99m d,I-HM-PAO: A new radiopharmaceutical for SPECT imaging of regional cerebral blood perfusion. J Nucl Med 28:191, 1987 157. Neumeyer JL, Wang S, Milius RA, et al: [123I]2carbomethoxy-3-(4-iodophenyl)tropane (B-ClT): High affinity SPECT radiotracer of monoamine reuptake sites in brain. J Med Chem 34:3144, 1991 158. Newberg A, Alavi A, Souder E, et al: Quantitative PET and MRI analysis in patients with primary progressive aphasia (PPA) [abstract]. J Nucl Med 33:857, 1992 159. Newton MR, Austin MC, Chan JG, et al: Ictal SPECT using technetium-99m-HMP AO: Methods for rapid preparation and optimal deployment of tracer during spontaneous seizures. J Nucl Med 34:666, 1993 160. Newton MR, Berkovic SF, Austin MC, et al: Dystonia, clinical lateralization, and regional blood flow changes in temporal lobe seizures. Neurology 42:371, 1992

650

MULLAN et al

161. O'Tuama LA, Treves ST, Larar JN, et al: Thallium-201 versus technetium-99m-MIBI SPECT in evaluation of childhood brain tumors: A w ithin-subject comparison . J Nucl Med 34:1045, 1993 162. Ohnishi T, Hoshi H, Jinnouchi S, et al: The utility of cerebral blood flow imaging in patients with the unique syndrome of progressive dementia with motor neuron disease. J Nucl Med 31:688, 1990 163. Oshima M, Tadokoro M, Sakuma S: Comparison of Tc-99m HMPAO fast SPECT w ith Tc-99m HMPAO conventional SPECT in patients with acute stroke. Clin Nucl Med 17:18, 1992 164. Overgaard J, Mosdal C, Tweed WA: Cerebral circulation after head injury. Part 3: Does reduced regional cerebral blood flow determine recovery of brain function after blunt head injury? J Neurosurg 55:63, 1981 165. Pacia SV, Bose A, Fayad P, et al: Single photon emission computed tomography (SPECT) in distal field infarction. Neurology 41:214, 1990 166. Pantano P, Baron JC, Samson Y, et al: Crossed cerebellar diaschisis: Further studies. Brain 109:677, 1986 167. Perani D, Di Piero V, Lucignani G, et al: Remote effects of subcortical cerebrovascular lesions: A SPECT cerebral perfusion study. J Cereb Blood Flow Metab 8:560, 1988 168. Perani D, Di Piero V, Vallar G, et al: Technetium99m HM-PAO SPECT study of regional cerebral perfusion in early Alzheimer's disease. J Nucl Med 29:1507, 1988 169. Podreka K, Suess E, Goldenberg G, et al: Initial experience with technetium -99m HM-PAO high resolution SPECT. J Nucl Med 28:1657, 1987 170. Pohl P, Vogl G, Fill H, et al: Single photon emission computed tomography in AIDS dementia complex. J Nucl Med 29:1382, 1988 171. Pupi A, De Cristofaro MT, Formiconi AR, et al: A brain phantom for studying contrast recovery in emission computerized tomography. Eur J Nucl Med 17:15, 1990 172. Reid RH, Guienchyn KY, Ballinger JR, et al: Cerebral perfusion imaging with technetium-99m HMPAO following cerebral trauma: Initial experience. Clin N ucl Med 15:383, 1990 173. Rowe CC: Interictal and postictal cerebral blood flow in temporal lobe epilepsy [thesis]. Melbourne, Australia, University of Melbourne, 1989 174. Rowe CC, Berkovic SF, Austin MC, et al: Patterns of postictal cerebral blood flow in temporal lobe epilep sy: Qualitative and quantitative analysis. Neurology 41:1096, 1991 175. Rowe CC, Berkovic SF, Sia ST, et al: Localization of epileptic foci with postictal single photon emission computed tomography. Ann Neural 26:660, 1989 176. Ruiz A, Ganz WI, Post MJ, et al: Use of thallium-201 brain SPECT to differentiate cerebral lymphoma from toxoplasma encephalitis in AIDS patients. AJNR Am J Neuroradiol 15:1885, 1994 177. Rutherford WH, Merrett JD, McDonald JR: Symptoms at one year following concussion from minor head injuries. Injury 10:225, 1979 178. Sacco RL, Foulkes MA, Mohr JP, et al: Determinants of early recurrence of cerebral infarction: The Stroke Data Bank. Stroke 20:983, 1989 179. Sawada H, Udaka F, Kameyama M, et al: SPECT findings in Parkinson's disease associated w ith dementia. J Neural Neuorosurg Psychiatry 65:960, 1992

180. Schmidt R: Comparison of m agnetic resonance imaging in Alzheimer's disease, vascular dementia and normal aging. Eur Neurol 32:164, 1992 181. Schroeder T: Hemodynamic significance of internal carotid artery disease. Acta Neural Scand 77:353, 1988 182. Schwartz RB, Carvalho PA, Alexander E, et al: Radiation necrosis vs high-grade recurrent glioma: Differentiation by using dual-isotope SPECT with 201Tl and 99mTc-HMPAO.AJNR AmJ Neuroradiol 12:1187, 1991 183. Seibyl JP, Marek KL, Quinlan D, et al: Decreased single-photon emission computed tomographic [123I]beta-CIT striatal uptake correlates with symptom severity in Parkinson's disease. Ann Neural 38:589, 1995 184. Sharp RF, SmithFW, Gemmell HG, et al: Technetium99m HM-PAO stereoisomers as potential agents for imaging regional cerebral blood flow: Human volunteer studies. J Nucl Med 27:171, 1986 185. Shen W, Lee BI, Park HM, et al: HIPDM-SPECT brain imaging in the presurgical evaluation of patients with intractable seizures. J Nucl Med 31:1280, 1990 186. Shimosegawa E, Hatazawa J, Inugami A, et al: Cerebral infarction within six hours of onset: Prediction of completed infarction w ith technetium-99m-HMPAO SPECT. J Nucl Med 35:1097, 1994 187. Smith FW, Gemmell HG, Sharp PF: The use of Tc99m-HM-PAO for the diagnosis of dementia. Nucl Med Commun 8:525, 1987 188. Smith FW, Beson JAO, Gemmell HG, et al: Technetium-99m-HMPAO imaging in patients with basal ganglia disease. Br J Radio! 61:914, 1988 189. Spampinato U, Habert MO, Mas JL, et al: (99mTc)HM-PAO SPECT and cognitive impairment in Parkinson's disease: A comparison w ith dementia of the Alzheimer type [see comments]. J Neural Neurosurg Psychiatry 54:787, 1991 190. Spencer SS: The relative contributions of MRI, SPECT, and PET imaging in epilepsy. Epilepsia 35(suppl 6):S72-S89, 1994 191. Sperling B, Lassen NA: Hyperfixation of HMPAO in subacute ischemic stroke leading to spuriously high estimates of cerebral blood flow by SPECT [see comments]. Stroke 24:193, 1993 192. Spieth M, Abelia E, Sutter C, et al: The importance of a lateral view in the evaluation of suspected brain death. Clin Nucl Med 20:965, 1995 193. Spieth M, Ansari AN, Kawada TK, et al: Direct comparison of Tc-99m DTPA and Tc-99m HMPAO for evaluating brain death. Clin Nucl Med 19:867, 1994 194. Stefan H, Bauer J, Feistel H, et al: Regional cerebral blood flow during focal seizures of temporal and frontocentral onset. Ann Neural 27:162, 1990 195. Stein SC, O'Malley KF, Ross SE: Is routine computed tomography scanning too expensive for mild head injury? Ann Emerg Med 20:1286, 1991 196. Stuss DT, Stethem LL, Hugenholtz H, et al: Traumatic brain injury: A comparison of three clinical tests, and analysis of recovery. Clin Neuropsychol 3:145, 1989 197. Tikofsky RS: Predicting the outcome in traumatic brain injury: What role for rCBF / SPECT? [editorial]. J Nucl Med 35:947, 1994 198. Tikofsky RS, H ellman RS: Brain single photon emission computed tomography: Newer activation and intervention studies. Semin Nucl Med 21:40, 1991 199. Tran Dink YR, Mamo H, Cervoni C, et al: Disturbances in the cerebral perfusion of human immune deficiency virus-I seropositive asymptomatic sub-

SINGLE PHOTON EMISSION COMPUTED TOMOGRAPHY BRAIN IMAGING

jects: A quantitative tomography study of 18 cases. 1990 Tsuchida T, Nishizawa S, Yonekura Y, et al: SPECT images of technetium-99m-ethyl cysteinate dimer in cerebrovascular diseases: Comparison w ith other cerebral perfusion tracers and PET. J Nucl Med 35:27, 1994 Uren RF, Magistretti PL, Royal HD, et al: Singlephoton emission computed tomography: A method of measuring cerebral blood flow in three dimensions (preliminary results of studies in patients with epilepsy and stroke). Med J Aust 1:411, 1983 Vallabhajosula S, Zimmerman RE, Picard M, et al: Technetium-99m ECO: A new brain agent. In vivo kinetics and biodistribution studies in normal human subjects. J Nucl Med 30:599, 1989 Veal! N, Mailett BL: Regional cerebral blood flow determination by Xe-133 inhalation and external recording: The effect of arterial recirculation. Clin Sci 30:353, 1966 Volkert WA, Hoffman TJ, Seger RM, et al: Tc 99 "'propylene amine oxime (Tc99 "'-PnAO): A potential brain radiopharmaceutical. Eur J Nucl Med 9:511, 1984 Wallner KE, Gallcich JH, Malkin MG, et al: Inability of computed tomography appearance of recurrent malignant astrocytoma to predict survival following reoperation. J Clin Oneal 7:1492, 1989 Walovitch RC, H ill TC, Garrity ST, et al: Characterization of technetium-99m-L,L-ECD for brain perfusion imaging, Part 1: Pharmacology of technetium-99m ECO in nonhuman primates. J Nucl Med 30:1892, 1989

J Nucl Med 31:1601, 200.

201.

202.

203.

204.

205.

206.

651

207. Weinberger DR, Gibson R, Coppola R, et al: The distribution of cerebral muscarinic acetylcholine receptors in vivo in patients with dementia: A controlled study with 123IQNB and single photon emission computed tomography [see comments]. Arch Neural 48:169, 1991 208. Weinberger DR, Jones D, Reba RC, et al: A comparison of FOG PET and IQNB SPECT in normal subjects and in patients with dementia. J Neuropsychiatry Clin Neurosci 4:239, 1992 209. Weinstein HC, Hijdra A, van Royen EA, et al: Determination of cerebral blood flow by SPECT: A valuable tool for the investigation of dementia. Clin Neurosurg 9:13, 1989 210. Weis M, Feistel H, Stefan H: Utility of ictal SPECT: Peri-ictal, post-ictal. Acta Neural Scand Suppl 152: 145, 1994 211. Williams DH, Levin HS, Eisenberg HM: Mild head injury classification. Neurosurgery 27:422, 1990 212. Winchell HS, Baldwin RM, Lin TH: Development of I-123-labeled amines for brain studies: Localization of I-123 iodophenylalkyl amines in rat brain. J Nucl Med 21:940, 1980 213. Wise RJS, Bernardi S, Frackowiak RSJ, et al: Serial observations on the pathophysiology of acute stroke: The transition from ischemia to infarction as reflected in regional oxygen extraction. Brain 106:197, 1983 214. Yonekura Y, Nishizawa S, Mukai T, et al: SPECT with 99 "'Tc-d,I-hexamethyl-propylene amine oxime (HMP AO) compared w ith regional cerebral blood flow measured by PET: Effects of linealization. J Cereb Blood Flow Metab 8:S82, 1988

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