Evolution of Brain Imaging Instrumentation

Evolution of Brain Imaging Instrumentation Tony Abraham, DO, and Janine Feng, MD Computed tomography (CT) and static magnetic resonance imaging (MRI) are now the most common imaging modalities used for anatomic evaluation of pathologic processes affecting the brain. By contrast, radionuclide-based methods, including planar imaging, single-photon emission computed tomography (SPECT), and positron emission tomography (PET), are the most widely used methods for evaluating brain function. SPECT and PET have been evolving for a longer time than CT and MRI and have made significant contributions to understanding brain function. The pioneering work on cerebral flow early in the last century laid the foundation of measurement with radioactive gases. This was initially performed with scintillation counters, which gave way to single, then multiple scintillation and multiprobe detectors. The invention of rectilinear scanners, MARK series, Anger cameras, and SPECT imaging further advanced nuclear medicine’s role in brain imaging. Measurement of regional cerebral blood flow by SPECT provides pathophysiologic information that directs patient management in a variety of central nervous disorders (CNS), with the greatest clinical impact found in cerebrovascular disease and seizure disorder. In the former, SPECT not only provides means of early detection and localization of acute strokes but can also direct thrombolysis and determine prognosis in the postcerebrovascular accident period. With respect to the latter, ictal SPECT can localize seizure foci so that patients with refractory disease can potentially undergo surgical resection of the affected area. In contrast to brain SPECT, brain PET images reflect regional cerebral metabolism. Because of neurovascular coupling, findings on SPECT and PET images are often comparable. PET, however, still has improved spatial resolution and is therefore more sensitive than SPECT, particularly in the evaluation of dementias. Brain PET instrumentation has greatly evolved from its infancy, when it was used in regional localization, to currently providing excellent resolution with imaging characteristics that can greatly impact clinical management. In addition, although ictal SPECT remains more sensitive than interictal PET for detection of seizure foci, the stringent conditions required for SPECT can be difficult to achieve, making interictal PET a very reasonable alternative. The clinical utility of PET and SPECT in neuropsychiatric and addictive disorders has not yet been defined, though a plethora of data exits. This arena of CNS disease has been the impetus for development of neurotransmitter-receptorspecific radioligands, which have already led to better understanding of dopaminergic, GABAergic, and serotonergic pathways. Another functional brain imaging technique that has gained broad acceptance since its invention in the early 1990s, is functional MRI, which indirectly measures CNS neuronal activity by evaluating oxygenation levels of cerebral vessels. Despite other recent related developments, such as MR spectroscopy, arterial spin labeling, and diffusion tensor imaging, nuclear medicine-based techniques remain clinically relevant and robust modalities, especially with the ever-expanding armamentarium of radiotracers and radioligands in conjunction with industry-driven improvements in image-analysis hardware and software. Semin Nucl Med 41:202-219 © 2011 Elsevier Inc. All rights reserved.

T Department of Nuclear Medicine, Montefiore Medical Center and The Albert Einstein College of Medicine, Bronx, NY. Address reprint requests to Tony Abraham, DO, Montefiore Medical Park, 1695A Eastchester Rd, Bronx, NY 10461. E-mail: toabraha@ montefiore.org; or Janine Feng, MD Montefiore Medical Park, 1695A Eastchester Rd, Bronx, NY 10461. E-mail: [email protected]

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0001-2998/11/$-see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1053/j.semnuclmed.2010.12.001

he radiolucent nature of brain tissues precludes their visualization with plain radiography (X-ray). The very first structural images of the brain are attributed to ventriculography,1 a technique developed in 1918 by an American neurosurgeon at Johns Hopkins, Walter Dandy (also known for describing the Dandy–Walker syndrome). This required drilling a cranial burr to access one of the lateral ventricles and draining a portion of cerebrospinal fluid (CSF), which

Evolution of brain imaging instrumentation was replaced with an equal volume of filtered air, to increase contrast and facilitate visualization of brain tissues on x-ray. A related and less invasive procedure, also used by Dandy, called pneumoencephalography,1 involved drainage of CSF and infusion of air, oxygen, or helium, via lumbar puncture. For the first time, these modalities allowed accurate localization of intracranial masses that could be potentially amenable to surgical resection. Although there were, not surprisingly, significant associated risks of hemorrhage, infection, and sequelae of abrupt changes in intracranial pressure, these techniques were not wholly abandoned until the advent of computed tomography (CT) in the 1970s. Thirty years earlier, Charles S. Roy and Charles S. Sherrington, pathologists at Cambridge University, were the first to characterize the direct relationship between cerebral neuronal activity and cerebral blood flow by the use of canine and rabbit models.2 They placed devices on the surfaces of the brains of anaesthetized dogs that measured changes in brain volume, a surrogate for changes in cerebral vascular volume or, cerebral blood flow. Through a variety of stimulation experiments, they found that “the brain possesses an intrinsic mechanism by which its vascular supply can be varied locally in correspondence with local variations in functional activity.” This concept, also known as neurovascular coupling, represents the basis upon which modern-day functional brain imaging techniques, such as single-photon emission computed tomography (SPECT), positron emission tomography (PET), and functional magnetic resonance imaging (fMRI) are founded. The next relevant seminal contribution in this area was by Seymour S. Kety and Carl S. Schmidt at University of Pennsylvania.3 They were the first to quantitate global cerebral blood flow in humans by the use of nitrous oxide (N2O), an inert gas that rapidly diffuses across the blood-brain barrier. The premise was that saturation of cerebral arterial blood with N2O is achieved more rapidly than saturation of venous blood, but that over time (10-15 min) equilibrium is established. The difference in the rates of change between arterial and venous concentrations of the gas at set time points following its inhalation before the steady state could then be used to calculate cerebral blood flow (CBF) with the use of Fick’s principle (used more familiarly in the calculation of cardiac output), in the equation3 shown below: CBF ⫽ 100 ⫻

兰

␭C␷(teq) teq

0

Ca(u) ⫺ Cv(u)du

Once CBF has been determined, oxygen and glucose use and CO2 production by the brain can also be calculated. In their studies, samples of arterial (femoral) and venous (internal jugular) blood were obtained 2, 4, 6, and 10 minutes after inhalation of N2O and evaluated for oxygen, CO2, and N2O concentrations. The applicability of their method relies on the assumption that the brain is homogeneous and that the blood obtained from the internal jugular vein represents mixed cerebral venous blood. Furthermore, the solubility coefficient, S, of N2O in blood and brain is assumed to be relatively unvarying in both normal and pathologic states. In

203 the clinical setting, this technique was used to assess CBF in patients who sustained head trauma and stroke.4,5 A study of patients with schizophrenia also used this technique.6 Interestingly, in their landmark paper, Kety and Schmidt3 alluded to the potential utility of radioactive gases in their technique, thereby providing the catalyst for the work of Landau et al7 and Lassen and Munck,9 both of whom pioneered work in measuring regional (not just global) CBF by using radioactive gases, thus providing the basis for functional brain imaging. The first ex vivo images of CBF were published in 1955 by Landau et al7 by the use of autoradiography to evaluate differences in CBF in cats at baseline (sedated) and in stimulated (awake and restrained) states with an intravenously administered radioactive gas (131I-labeled tri-iodofluoromethane) in solution. The cats were sacrificed 1 minute after infusion; their brains were harvested, frozen, then sectioned at 5-mm intervals and stored in liquid nitrogen. Slices were then placed in between layers of X-ray film and stored in a dark room for 10 hours. Images showed that regional CBF was increased in the awake versus sedated state. The radioactivity in specific brain regions were counted, compared with a 131I standard, and the regional blood flow could then be calculated. They furthered their work with a variety of different radiotracers, including 131I-antipyrine and 14C-antipyrine, the latter of which provided greater resolution and a longer half-life, as well as the ability to collect specimens and produce images at room temperature.8 In the same year, Lassen and Munck9 performed in vivo CBF studies in humans, modifying Kety and Schmidt’s technique by replacing N2O gas with atmospheric air containing trace amounts of krypton (85Kr). This was a significant improvement over the cumbersome N2O measurements because they relied simply on measurements of radioactivity present in the collected arterial and venous samples with a scintillation counter. In a later modification of the original method (1957), Munck and Lassen10 collected venous blood from bilateral internal jugular veins rather than from just one side to more accurately reflect global blood flow and oxygen use. The next advance in this area was the measurement of regional cerebral perfusion.11 This was achieved by placing one or more lead-collimated scintillation detectors on the scalp overlying the region(s) of interest in the brain to determine radiotracer accumulation and clearance from those particular areas of intraarterially injected radiotracer (either 85K or 133Xe dissolved in saline solution). Semilogarithmic elimination curves (Fig 1) were generated from the acquired counts allowing for calculation of regional cerebral blood flow by the use of equation11: f ⬵ ␭ · H (10) ⁄ A (10) ml ⁄ g ⁄ min Multiprobe scintillation detectors that allowed for simultaneous measurements of blood flow of individual regions of the cerebral cortex were used later.12 Both of the radiotracers used in these studies have advantages and disadvantages.13 For example, 85Kr provides greater energy (500 keV vs 81 keV for 133Xe), thereby providing better definition of depth

T. Abraham and J. Feng

204

reasons and because it may be administered intraarterially or via inhalation.

Brain Imaging Systems

Figure 1 Oscilloscope display of washout from region over temporal area. First 20 points represent 0.5-second intervals. Non-nutritional spike (intravascular activity) is seen in first several seconds. (Reproduced with permission from Holman BL: Concepts and clinical utility of the measurement of cerebral blood flow. Semin Nucl Med 6:233-251, 1976.)

and minimizing the effects of Compton scatter from other regions, but is costly. 133Xe, by contrast, exhibits a greater count rate per milliliter of solution and is therefore more accurate for counting of small regions of interest; in addition, it provides improved spatial resolution. 133Xe ultimately proved to be more satisfactory both for the aforementioned

Instruments for dedicated brain SPECT imaging have undergone significant improvements in spatial resolution. Along with these advances, industry-driven development of image processing software and hardware has led to increased reliability of computer quantitation and data analysis. Development of dedicated tomographic brain imaging systems in nuclear medicine parallels that of instrumentation used to image the rest of the body. Several important instruments antedate tomographic imaging. One of these, the Geiger-Mueller counter (or “electron counting tube”), developed in 1928, was the first means by which radioactivity emitted from the body was measured.14,15 It was simply held over the body region of interest and radioactivity levels were recorded as a series of clicks, varying in frequency depending on the amount of energy emitted. In 1949, Benedict Cassen developed the rectilinear scanner, another landmark device—the first to create a visual representation of energy emitted from a radioactive source within the body.16 As the machine moved laterally across the body, a tapper created dots on a piece of paper to reflect the radioactivity present (Fig. 2). David Kuhl improved on this method by connecting the scanner to a photorecorder so the images were produced on x-ray film in shades of gray, thereby allowing for direct comparisons with plain radiographs of the same region.17 Finally, the Anger scintillation camera, destined to become the workhorse of nuclear medicine, was invented by Hal O. Anger in 1957.18

Figure 2 Benedict Cassen and the first automated rectilinear scanner circa 1950. (A) Photoscan of the brain in a patient with a grade 3 astrocytoma. (B) Note “doughnut sign.” (Reproduced with permission from Blahd.17)

Evolution of brain imaging instrumentation

1980 Tomomatic-64, (modification of D-CT or D-SPECT) Medimatic A/S Inc. Denmark and Irvine, CA20,22,23,26,27,30

CT, computed tomography; PET, position emission tomography; PMT, photomultiplier tubes; SPECT, single-photon emission computed tomography.

17-23/90,000 per slice for Tomomatic and 55,000 per slice for D-CAT

17/15,400 Mark IV As above

1969-75

Xe-133, Tc99m, I-123, I-131 Xe-133, Tc99m, I-123, I-131 Xe-133, Tc99m, I-123, I-131 Mark III As above

1965-68

Xe-133, Tc99m, I-123, I-131 Mark II Kuhl and Edwards, University of Pennsylvania19,20,22,23,30

1959-63

Three focused collimators (high sensitivity dynamic and static and high resolution dynamic)

Eight mulithole focused

4 NaI in translate-rotate sequence 32 (8 NaI crystals arranged in a square) Four banks of 16 detectors, each bank with 3 rows of PMTs

Focused

241 Am transmission source, a predecessor of CT, SPECT/CT, and PET/CT Orthogonal tangent correction OTC; used for brain only Three slices can be sampled at once with fast rotation

Special Features Collimation

Focused 2 NaI in translate-rotate sequence

Number of Detectors Resolution (mm)/ Sensitivity (cps) Capabilities (Radiotracers) Year Produced Name

The literature has shown that there is significant inter- and intraobserver variability in the interpretation of SPECT brain scans. Stockbridge et al43 at Harborview Medical Center, University of Washington, randomly chose 48 brain SPECT scans to be interpreted by 3 readers on 2 separate occasions. Intraobserver variability ranged from 65% to 100% and interobserver variability ranged from 29% to 100%. Hence, there is an impetus to enhance the visual impression with quantitative analysis, with the goal of providing a more complete diagnosis. In parallel with the development of greaterresolution gamma cameras during the past 20 years, increasingly sophisticated software for image registration and statistical image analysis has also emerged. Image registration corrects for variability in position and shape of the brain so that serial images can be appropriately aligned with one another or to a template. Without such an alignment, statistical analysis of the generated images is precluded. This process also minimizes differences in images resulting from variable handling of radiotracer from one sub-

Company/Site of Production

Image Analysis

Table 1 Tomographic (“Noncamera-Based”) Systems: Rotating Detector Arrays

Its large detector face was able to capture emitted energy from larger areas of the body simultaneously, thus increasing the efficiency of gamma photon counting. In the late 1950s through the early 1990s there was a proliferation of new tomographic and camera-based instruments, many of which were dedicated to brain imaging. In 1959, David Kuhl and Roy Edwards invented the first of these devices, called the Mark II.19 Unlike its successors Mark III and IV, which were designed for dedicated brain imaging, the Mark II had the mechanical flexibility to image different parts of the body. Despite this, the most significant work generated by this instrument was the imaging of brain tumors. SPECT systems, whether for whole body or dedicated brain imaging, generally are composed of single or multiple radiation detectors organized in a specific configuration, a mechanism for rotating the detector(s) around the body part of interest, and collimators to acquire data from different projections and optimized to the region(s) of interest.20-23 SPECT instruments are of 3 general types: multidetector arrays (either rotating or fixed), scintillation (gamma) cameras, and hybrid systems representing novel designs incorporating the 2 former features. The primary advantages of the former are high count-rate capability and high sensitivity, but these scanners are not able to acquire more than a few tomographic slices through the body in a noncontiguous fashion. They are also more costly than camera-based systems. The latter provide the ability to acquire contiguous tomographic slices over the area of interest. Before the development of 2to 4-headed cameras, camera-based systems were plagued by low-count rate capability and low sensitivity, but the use of multiple heads has eliminated these problems.20-23 In Tables 1-5 are shown examples (not meant to be comprehensive) of SPECT instruments that have been developed during the past 50 years, including some of their specifications.12,18-42 Figures 3 and 4 show diagrams of some of the cameras listed in Tables 1-5.

205

T. Abraham and J. Feng Produces 4 orthogonal 2-D images simultaneously Continuously, rotating with 4 collimator quadrants each with multiple modules; collimator lies within the crystal 5-8/3000

MUMPI, Missouri University multiplane imager.

Xe-133, Tc99m, I-123, I-131 MUMPI Missouri University20,31

1984

HEADTOME I-III Shimadzu20,29,30,36

1982-85

Xe-133, Tc99m, I-123, I-131

10-20/9800 for Xe-133 and 21,000 for Tc99m

Three circular rings of NaI crystals, each ring with 64 detectors Single cylindrical NaI detector

34-cm rotating lead aperture ring with 10-12 slits; parallel lead foil rings Varying pitch collimator 11 2-D NaI camera modules in a 50-cm ring 8-10/maximum of 715/ min/␮Ci Xe-133, Tc99m, I-123, I-131 1988 Sprint I and II University of Michigan, W.L. Rogers23-25,29,31

Resolution (mm)/ Sensitivity (cps) Capabilities (Radiotracers) Year Produced Name Company/Site of Production

Table 2 Tomographic (“Noncamera-Based”) Systems: Fixed Detector Research Systems

Number of Detectors

Collimation

Special Features

Available only in Japan

206

ject to another. Linear registration is an automated method to minimize either the measured difference or ratio between images acquired from the same imaging modality.44 Each image is iteratively modified to minimize either of these parameters. Newer applications of this method include registration of different sets of dynamic images, such as those acquired for kinetics of neuroreceptor binding. Acton et al,45 for example, used principal component analysis to coregistered images acquired for evaluation of D2 receptor kinetics (imaging performed with SME 810 brain scanner). This resulted in a 25% decrease in error in x and y axes compared with other registration methods. Another mode of registration is to use a standard brain template image onto which acquired patient brain images are “warped” to conform to it. This technique is relatively new and must be used with caution because overuse can lead to removal of the abnormalities for which the imaging study is being performed.46 Persistent challenges in image analysis include regions of interest (ROI) placement and image normalization. ROIs are not standardized and exhibit variability in shape, size, and location, depending on the disease entity. Coregistration of SPECT and PET with anatomic imaging (CT or MRI) has increased the accuracy with which ROIs are placed.47,48 Normalization of the ROI data are necessary so that changes from one patient to another truly reflect differences in the disease of interest, rather than differences between the subjects related to technique, scanner type, and inherent biology. Normalization may be performed using a global reference (whole-brain activity, activity in one slice of the brain, or sum or activity in all ROIs); this method is more applicable when the expected alterations are small and focal.49 Normalization can also be made to a part of the brain presumably spared by the disease entity, though this is challenging in ictal and peri-ictal studies of epilepsy. The cerebellum has most commonly been used as the reference region, particularly when studying Alzheimer’s disease50; occipital cortex and basal ganglia have been less frequently used. The current “gold standard” of statistical image analysis is statistical parametric mapping (SPM), particularly for receptor studies. In simple terms, SPECT and PET images are parametric maps in which composite pixels and voxels representing radioactivity (counts) are distributed in a pattern that mirrors biological behavior. In contrast, with SPM, pixels and voxels reflect regions in which differences between 2 sets of images achieve significance by exceeding a predetermined threshold. Although SPM has been used primarily for brain PET and fMRI activation studies,51 they have also been used in studies of dementia. For example, Kogure et al52 at Tokyo Medical University used SPM to study changes in regional cerebral blood flow (rCBF) over time in 32 patients with mild cognitive impairment (MCI) that were ultimately diagnosed with Alzheimer’s disease (AD) within the 2-year follow-up period. The 32 subjects and 45 control patients underwent 99mTc-ECD brain SPECT (using the 3-headed MultiSPECT 3), with one additional set of SPECT images acquired in the 32 subjects after a mean interval of 15 months. Initial images showed hypoperfusion of the poste-

MAP recon, similar to that of scanning microscopes requiring special gamma lenses

Cerebrovascular disorders, including transient ischemic attacks, stroke, subarachnoid hemorrhage, and arteriovenous malformation have been evaluated with PET and SPECT. SPECT is used in the setting of acute stroke for: (1) early localization of the affected region, (2) identification of patients amenable to thrombolytic therapy, and (3) prognostication of outcome. Scintigraphic findings of hypoperfusion in acute stroke precede those of CT and MRI. Typically, at 8 hours after onset of acute stroke, 90% of SPECT images will demonstrate a perfusion abnormality whereas only 20% of CT scans will be positive.53 By 72 hours after an acute event, anatomic and functional imaging modalities are comparable with one another in sensitivity; the disadvantages of SPECT brain perfusion imaging include (1) inability to differentiate hemorrhagic versus embolic stroke and (2) onset of luxury perfusion (perfusion of brain that has undergone infarction) as early as 5 days after acute cerebrovascular accident (CVA), resulting in false impression of viability. SPECT studies that use 133Xe are particularly susceptible to this misinterpretation, whereas those that use 99mTc-ECD are less so.54,55 In patients imaged in the subacute phase of stroke (11-23 days), 133Xe-images clearly showed perfusion to be normal or increased in the affected area whereas 99mTc-ECD images correctly demonstrated decreased radiotracer activity. Attempts have been made since the 1990s to develop guidelines for triaging patients who would be potentially amenable to thrombolytic therapy after 5 acute stroke. On the basis of SPECT perfusion studies, there are 3 categories into which these patients fall: (1) those without rCBF who are therefore unlikely to derive benefit from thrombolysis, (2) patients with normal rCBF in whom there is no need for therapy, and (3) patients with diminished but not absent rCBF who could benefit from thrombolysis. On the basis of the large trials of 1990s, there is a 3-hour window from onset of CVA within which administration of thrombolytic therapy is potentially beneficial. Beyond this 3-hour time frame, the risks of hemorrhage, cerebral edema, and death outweigh clinical benefit.56 Initial triage algorithms required only CT scanning to exclude hemorrhagic stroke but never incorporated functional imaging modalities. Ueda et al57 used 99mTchexamethylpropyleneamine oxime (HMPAO) imaged with either the 4 headed Hitachi (2000H)-40 or Toshiba GCA602A and determined that if the ratio of regional to cerebellar blood flow was ⬎35% and ⬍55%, thrombolytic therapy was likely to salvage cerebral parenchyma at risk if administered within 5 hours of the acute event. By contrast, increased hemorrhage risk with thrombolysis was seen if the regional blood flow was ⬍35% of cerebellar perfusion. Implementation of these guidelines has not yet become universal because of maintenance of the 3-hour window coupled

Twelve detector heads

Clinical Applications

PMT, photomultiplier tubes.

1988

2004

CeraSPECT/ ASPECT3000

Neurofocus

Xe-133, Tc99m, I-123, I-131, In-111 Xe-133, Tc99m, I-123, I-131, In-111

5.3-7.7/220 cps per Mbq or 27 cps per slice 3/-

Three rings with 21 PMTs per ring

Dedicated brain

Three annular parallel collimators in continuous rotation Eight hundred-hole, long-bore pointfocused collimators, moving side to side and in and out

207 rior cingulated gyrus and precuneus; use of SPM to compare initial and subsequent images resulted in detection of an interval severe decline in perfusion in the left hippocampus and parahippocampal gyrus. The latter findings may have been missed with traditional ROI methods.

Genna and Smith with digital scintigraphics21,31,32,38 Neurophysics21,42

Capabilities Year Produced Name Company/Site of Production

Table 3 Tomographic (“Noncamera-Based”) Systems: Fixed Ring Arrays

Resolution (mm)/ Sensitivity (cps)

Number of Detectors

Collimation

Special Features

Evolution of brain imaging instrumentation

T. Abraham and J. Feng

HMS, Harvard Multidetector Scanner; rCBF, regional cerebral blood flow.

254 multidetector scanner University of Copenhagen12

1977

Xe-133, Tc99m, Hg-197

9/1,000,000

254

2 (parallel and converging)

Scanning occurs radially and tangentially, requiring special reconstruction up to 8 slices imaged at once Designed mainly for rCBF studies 12 highly focused collimators 2-32 for HMS and 12 for CLEON, radially distributed 10-15/14000 F-18, Tc99m, I-131; NOT Xe-133 1979 HMS, a.k.a. CLEON 710, and SME-810 Harvard and Union Carbide/ Strichman Corporation and J and P Ltd20,22,28-30

Capabilities Year Produced Name Company/Site of Production

Table 4 Tomographic (“Noncamera-Based”) Systems: Nonrotating, Multidetector Arrays

Resolution(mm)/ Sensitivity (cps)

Number of Detectors

Collimation

Special Features

208

with the time required to complete SPECT imaging, which can be more than 1 hour from patient preparation to scan completion.58 Predicting the outcome of acute stroke shortly after its occurrence is important in directing medical management. By using 99mTc-HMPAO imaged with the GE 400 AC gamma camera, Mountz et al59 was the first group to show that the ratio of the SPECT defect volume relative to the volume of the anatomic defect (on CT) correlates with clinical outcome. They found that a larger ratio is associated with improved outcome and a smaller ratio with poorer outcomes. The relatively larger size of the scintigraphic perfusion defect compared with the anatomic defect represents not only the region of true infarction but also a penumbra of reversibly ischemic, vulnerable tissue that can recover function and lead to clinical improvement following the acute event. Comparably, sized perfusion and anatomic defects represent absence of salvageable tissue and have a decreased likelihood of recovery. In general, SPECT studies performed more temporally proximate to the acute CVA have more robust predictive value than those performed later and can improve the predictive power of clinical prognostic algorithms, such as the Canadian Neurologic Scale and National Institutes of Health stroke scale. For example, Baird et al60 performed SPECT imaging in 53 patients at 24 and 48 hours after acute CVA with the GE Starcam 400 AC (single-head gamma camera) and concluded that improvement of rCBF within the first 48 hours after CVA was an independent predictor of improved outcome (P ⬍ 0.01); this study provided support for the role of thrombolytic therapy in the appropriate clinical setting. Alzheimer disease (AD) is the most common cause of dementia, accounting for 65% of cases. The typical scintigraphic features include decreased metabolism and perfusion in the temporo-parietal region and posterior cingulate gyrus, accompanied by decreases in the frontal regions later in the disease course (ie, not seen in the absence of temporal and parietal abnormalities). Basal ganglia, thalami, cerebellum, and sensorimotor and visual cortices are relatively spared. These changes are more readily seen on PET versus SPECT; PET provides improved spatial resolution and is also not limited by occasional uncoupling of metabolism from perfusion.61 Overall, there is an increased diagnostic accuracy for AD of 15%-20% with PET over SPECT as reported by Messa et al62 with the CersSPECT brain imager. Head-to-head comparisons have shown greatest concordance in the posterior cingulate gyrus and temporoparietal region with r of 0.90, when statistical parametric mapping was used (images acquired with PRISM 3000). Discordance was seen in orbitofrontal, temporobasal, parahippocampal, and midcingulate areas. In addition, correlation of disease severity with scintigraphic abnormalities was more robust with PET than with SPECT. Most importantly, the magnitude of decreased metabolism was larger than that of decreased perfusion, allowing for the possibility of disease detection earlier in its course with PET. SPECT imaging, however, is more widely available and less expensive than PET, thus ensuring that it remains a via-

Company/Site of Production

Name

Year Produced

Capabilities

University of Texas Southwestern Medical School and picker (Ohio imaging) and Technicare21,29,39 Trionix and Duke University29 GE35

PRISM3000XP

1987

Xe-133, Tc99m, I-123, I-131

Triad 88

1989

Neurocam

1991

Summit/Hitachi33

NeuroSPECT2000H

1989

Toshiba34

GCA-9300A

1992

Siemens37

MultiSPECT3

1993

NeuroLogica41

inSPira HD

2009

Mediso40

Nucline x-Ring-4R

2002

Tc99m, I-123, I-131 Tc99m, I-123. Xe-133 Tc99m, I-123, I-131 Tc99m, I-123, I-131 Tc99m, I-123, I-131 Tc99m, TL-201, I-123, In-111, Xe-133 Tc99m, I-123, I-131, F-18

Resolution(mm)/ Sensitivity (cps) 7/16,500

7.3/106 Per ␮Ci/ min 9-10/30000

Number of Heads Three-headed camera

9-13/72000 7.8/50,000

Three-headed camera

2.3/200,000

Fan-beam

Three-headed camera Three-headed camera with 27 PMTs Four-headed camera

8.5/380 Per s per MBq 3/11,000 Per s per ␮Ci

Collimation

Special Features Also capable of F-18 imaging with appropriate collimators not dedicated for brain

Evolution of brain imaging instrumentation

Table 5 Gamma Camera Systems

Not dedicated brain GP and HR

Dedicated brain

LEHR. LEGP, LEHS, MEGP Fan beam

Dedicated brain

2-3 heads

Not dedicated brain Not dedicated brain

72 NaI detectors PMTs

Twenty-four focused collimators

Battery-powered and portable

Four-headed camera

LEAP, LEHR, LEUHR

Hybrid SPECT/PET system

GP, general purpose; HR, high resolution; LEAP, low energy all purpose; LEHR, low-energy high-resolution; LEUHR, low energy ultra-high resolution; MEGP, medium energy all purpose; PMT, photomultiplier tubes; SPECT/PET, single-photon emission computed tomography/positron emission tomography.

209

210

Figure 3 Diagram of Missouri University multiplane imager (MUMPI) for brain imaging. (Reproduced with permission from Heller and Goodwin.153)

ble imaging modality for dementia. On the basis of 5 seminal studies of SPECT in AD, its overall diagnostic sensitivity is 77% (63%-91%) and specificity, 82% (73%-93%), respectively.63 These data, however, are more appropriately interpreted on an individual basis because of differences in: (1) disease severity and duration, (2) diagnostic standard (histology; autopsy or brain biopsy vs clinical), and (3) radiotracers and scanner types. For example, Bonte et al64 were the only investigators to measure rCBF with both inhaled 133Xe and 99mTc-HMPAO. The former was imaged with the highly sensitive Tomomatic scanner and the latter with the 3-headed PRISM 3000 gamma camera. A total of 423 patients with suspected AD were enrolled; 261 underwent 133Xe-studies and 162 99mTc-HMPAO studies. Time from imaging to histologic diagnosis was highly variable (1-85 months). Sensitivity was found to be 86% and specificity 73%. 133Xe studies were more sensitive than 99mTc-HMPAO images (92% vs 80%) but

Figure 4 Schematic diagram of SPRINT ring aperture system illustrating the slits (Ws), object to be imaged, and the ring of 78 gamma detectors. (Reproduced with permission of Lippincott Williams & Wilkins from Mountz.25)

T. Abraham and J. Feng this was not statistically significant (P ⫽ 0.29). Another study in which autopsy was used as the diagnostic standard for AD was conducted by Jagust et al,65 Unlike the previous, in which enrolled patients were at variable stages of disease and in which imaging was performed with the use of a highresolution brain-dedicated gamma camera, in this study all 70 patients were in late stages of disease (average time from imaging to death was 15 months). Imaging was performed with the GE400XCT (a single-head rotating gamma camera); the authors achieved a sensitivity of 63% and specificity of 93%. Biochemical and genetic markers conferring high risk of AD development are now being compared with scintigraphic findings. Okamura et al66 performed SPECT of patients with suspected AD and patients with MCI by using the perfusion tracer 123I-IMP. Comparison of scintigraphic findings with cerebrospinal fluid tau protein concentrations showed significantly lower ratios of tau/rCBF in the posterior cingulate gyrus of patients with AD and progressive (vs stable) MCI. Brain SPECT and PET are useful in managing patients with partial seizures refractory to medical therapy (up to 40%). These functional imaging techniques are used to localize seizure foci that may be amenable to resection with the goal of achieving a seizure-free state.67 In specialized neurosurgical centers 70% of patients with temporal lobe epilepsy (TLE) can become seizure-free, although in extratemporal lobe epilepsy (ETLE) the success rate is diminished at 40%-50%.68 Ictal SPECT studies are performed by injection of radiotracer ideally within 30 seconds of seizure onset to capture hyperperfusion associated with increased activity in the seizure focus. For TLE, typical scintigraphic findings include increased radiotracer activity in the medial and anterior temporal lobe, ipsilateral basal ganglia, thalamus, insular cortex, and basal frontal lobe.69 If a seizure becomes generalized, the entire affected hemisphere may demonstrate increased perfusion. In studies comprising 500⫹ patients with partial seizures, ictal SPECT correctly detected the seizure focus in 90% of cases70 with incorrect laterality in 5%. This is in contrast to post/peri-ictal SPECT, in which correct location was noted in 70% with 5% error in laterality.71 Postictal SPECT, in brief, is usually characterized by hypoperfusion surrounding the seizure focus. Greater accuracy of ictal versus postictal SPECT is attributable to variability in duration of postictal change and in the timing when postictal pattern superseded the ictal pattern.71 Interictal SPECT generally shows hypoperfusion in the seizure focus but has limited diagnostic accuracy (correct localization in 55% with error in laterality of 10%)71 and is therefore used mainly as a baseline study with which ictal SPECT images are compared. PET and SPECT have comparable sensitivities for detecting seizure foci in TLE (89% for SPECT and 80% for PET)72 and ETLE (56% for both). The main utility of SPECT in managing patients with head trauma is in cases of suspected “mild” traumatic brain injury (MTBI) in whom extent of injury and possible sequelae are difficult to predict solely on a clinical basis. Extensive literature review by Davalos and Bennett73 on imaging of TBI from 1996 to 2000 found that SPECT can be useful for both diagnosis and prognosis of MTBI (normal SPECT has a high neg-

Evolution of brain imaging instrumentation ative predictive value for subsequent neurologic impairment). In addition, abnormalities may often be detected before their appearance on CT or MRI. For example, Vamey et al,74 using the NeuroSPECT dedicated brain scanner, found that hypoperfusion (especially in the mesial temporal regions) was seen on SPECT without corresponding abnormalities on CT or MRI. Similar findings were described by Cihangiroglu et al at the University of Chicago.75 This might explain the not infrequent association of memory impairment with MTBI. In light of observations that Parkinsonian features have been seen in individuals following TBI, Donnemiller et al76 studied the dopaminergic system in such patients compared with a normal cohort. SPECT imaging with the 3-headed PRISM 3000XP demonstrated a statistically significant decrease in dopamine transporter (DAT) and D2 receptor binding in the TBI cohort. If a causative association between the imaging and clinical findings exists, there is a potential role for the use of levodopa in select patients with TBI. Currently, there is a trend toward computer quantitation analysis of brain perfusion to enhance the utility of SPECT and PET in evaluation of patients with TBI. SPM, brain analysis of SPECT studies, and voxel-based analysis have been used by several groups to show that hypoperfusion of the medial frontal gyrus, cingulated gyrus, and hippocampus are not merely subjective visual interpretations but, quantifiable abnormalities. Brain SPECT and PET have been used for evaluation of nearly all the DSM-IV⫺defined psychiatric disorders, especially during the past 10 years. Anxiety disorders (obsessive compulsive disorder, panic disorder, posttraumatic stress disorder, etc), affective disorders (depression and bipolar disorder), and schizophrenia have the largest body of literature documenting associated scintigraphic findings. In general, for all of these entities, abnormalities of perfusion and metabolism in certain regions of the brain have been identified. The relative absence of such derangements in healthy control subjects has led to the belief that these areas are pathologic in the presence of disease but provide limited understanding of etiology. Development of several neurotransmitter-receptorspecific radioligands for both PET and SPECT specific for dopaminergic, GABAergic, and serotonergic receptors has furthered investigation of pathophysiology of these diagnostically and therapeutically challenging disorders. Discussion of brain imaging for all the aforementioned disorders is beyond the scope of this review, which will therefore focus on specific findings related to schizophrenia. A progressively debilitating psychosis affecting 1% of the population, schizophrenia is characterized by visual/auditory hallucinations, disorders of thought, and cognitive deficits. In 20%-30% of patients, current antipsychotic medications are only partially effective. Autopsy and MRI studies have documented anatomic abnormalities in patients with schizophrenia, including lateral ventricular enlargement and decreased size of the hippocampus and entorhinal cortex. Abnormalities of the frontal lobe have also been noted on MRI. Interestingly, one of the first scintigraphic studies of cerebral blood flow in schizophrenic patients, performed by Ingvar and Franzen77 also demonstrated relative hypoperfusion of

211 the frontal lobe using inhaled 133Xe and a 32-detector camera. This finding was replicated in 18F-FDG PET studies, including those performed by Gur et al78 and Early et al,79 who also noted increased metabolism in the left cerebral hemisphere and the left globus pallidus in particular. Kishimoto et al80 correlated clinical manifestations of schizophrenia with hypometabolism in different regions of the brain; patients with delusions and hallucinations were more likely to have decreased parietal metabolic activity whereas patients with flat affect had decreased frontal cortical metabolism. Current trends involve not only observing differences in perfusion and metabolism in treated and untreated schizophrenic patients but also when these patients perform specific tasks or subjected to certain external challenges. The latter has the goal of better correlating performance deficits with abnormalities in specific regions of the brain. Because fMRI studies can be performed repeatedly in the same individual and does not entail radiation exposure, this technique has slowly replaced scintigraphic techniques in this arena. SPECT and PET remain viable imaging modalities in schizophrenia because of new radioligands that specifically target neurotransmitter receptors. Hyperactivity of the neostriatal dopaminergic pathway is currently the lead hypothesis for pathogenesis of schizophrenia. The first study to demonstrate increased neostriatal activity used 77Br-bromospiperone imaged with a gamma camera (although PET is the more commonly used imaging modality for this tracer).81 PET tracer 11C raclopride and SPECT tracers 123I-iodo-methoxybenzamide and 123I-epidepride82 are high-affinity D2/D3 receptor ligands that have shown additional abnormalities in dopaminergic receptors in the basal ganglia and nucleus accumbens.82 Collectively, the data suggest only mildly increased numbers of D2 receptors in the neostriatum of schizophrenic patients versus normal controls.83 There have, however, been some unexpected findings; for example, increased D2 receptor density has been seen in the left hemisphere in male schizophrenics84 and in the basal ganglia of patients with stereotypy. Investigation of abnormalities in GABA and serotonin receptors in schizophrenia is ongoing, with introduction of SPECT radioligands 123I iomazenil85 and 123I-5-R-91150, respectively.86 SPECT and PET remain unable to accurately predict who will develop an addictive disorder and are not able to specifically diagnose individuals clinically known to have addictive disorders. They have, however, both helped in the further understanding of the pathophysiology of addiction, defined by the DSM-IV as “a maladaptive pattern of substance use of activity leading to clinically significant impairment or distress.” It is known that addiction “begins” in the dopaminergic mesostriatal pathway; with the most commonly encountered substances of abuse being characterized by persistently increased dopamine secretion into the extracellular space. Other neurotransmitters, including serotonin, GABA, acetylcholine, corticotrophin-releasing hormone, etc., promote and sustain the addiction and also play a role in its physical and emotional sequelae. The most significant contributions of SPECT imaging in understanding addictive behaviors has been through the use

212 of 123I-iodo-methoxybenzamide, a tracer that binds to the D2 dopamine receptors at the postsynaptic receptor. 123I-labeled 2beta carbomethoxy-3beta-(4-iodophenyl)tropane has also been used and targets the DAT. The premise is that because addictive substances either directly or indirectly increase dopamine levels, dopamine receptors, and transport systems will become less readily available as a compensatory mechanism. Laruelle et al87, using the Picker 3000 SPECT, found that infusion of amphetamine lead to a decrease in the D2 receptors in the striatal region. Clinically, subjects experienced restlessness, euphoria, and alertness during the infusion. Similarly, Malison et al88 at Yale found that DAT availability was diminished after the administration of cocaine when they used the brain-dedicated CeraSPECT system. Conversely, in the withdrawal state, DAT levels normalized. After the withdrawal period during abstinence, it is assumed that a new neurologic baseline is achieved. In this phase, SPECT imaging has shown variable relative hypoperfusion in the temporal cortex, basal ganglia, and frontal cortex that may persist as long as 4-6 months after the withdrawal period. In addition, several researchers have shown corresponding decreases in D2 receptors in the same regions in which perfusion and glucose metabolism are diminished. This finding has led to the hypothesis that dopamine aggravates the process of addiction by altering function of brain regions responsible for self-control and motivation.89 In addition to disruptions in the dopaminergic system, Heinz et al,90 found decreased serotonin transporters in the brainstem when they used 123I-beta 2beta carbomethoxy3beta-(4-iodophenyl)tropane imaged with the CeraSPECT in patients abstaining from both alcohol and methamphetamines. Currently, fMRI is on the verge of superseding SPECT and PET with respect to the real-time evaluation of the effects of drug use on cognition and impulse behaviors because of its superior temporal resolution. The true strength of both SPECT and PET lies in the continual emergence of novel radiotracers that allow imaging of receptor systems, such as 123I-FP-TZTP and 123I-5-i-A-85530 specific for the Ach receptor and 123I-5-i-R91150 and 123I ketanserin, specific for serotonin.86

Positron Emission Tomography PET has been a key noninvasive imaging modality to evaluate cerebral processes, such as blood flow, cerebral metabolic rate for glucose, neurotransmitter, enzymatic, and receptor binding activity. The initial application of PET in molecular imaging led to its clinical applications in the brain, such as tumor localization, epilepsy, stroke, various forms of dementia (eg, AD), and neuropsychiatric diseases. It also has been used in assessment of the pharmacokinetics and pharmacotheraputies of neurologic drugs. Although most PET studies today focus on oncological imaging from the skull base to midthighs, its value as a dedicated brain imaging device cannot be denied but is often underused by clinicians. Brain imaging has been a cornerstone of PET since its advent; however, it has been relegated to a great extent to the research arena.

T. Abraham and J. Feng

Figure 5 Illustration of the significant improvement in clinical FDG brain PET image quality and spatial resolution resulting from the improvement in scanner performance for each generation during the past 3 decades. (From Siemens Medical Solutions, Knoxville, TN); reproduced with permission from Zaidi et al.152)

An ideally designed PET instrument would have high resolution, sensitivity, and count rates, with low dead time losses and random and scatter events. These characteristics result from physical factors, some of which are interdependent, whereas others work counter to each other. For example, a small crystal size leads to better resolution but also leads to a smaller geometry, permitting higher sensitivity. However, the smaller design then leads to more random and scatter events. In addition, the size of the human head permits the development of dedicated brain imaging devices. A dedicated brain PET can provide many advantages over whole-body PET scanners, such as high spatial resolution and counting rate dynamics that help quantify physiological events. The small ring design also provides high sensitivity. A small detector camera with fewer photomultiplier tubes (PMTs) can cost less and can serve as a workhorse for dedicated brain imaging as long as a referral base has been established. The disadvantages include increased scatter and random events, a decrease in spatial resolution as the sensitivity increases and higher parallax or depth of interaction (DOI) error, which also reduces spatial resolution. The parallax error increases as the ring diameter decreases, because of coincidence events occurring off-center that enter the detector at oblique angles and can result in significant differences be-

Evolution of brain imaging instrumentation

213

Figure 6 Photographs of dedicated brain PET scanners showing (A) the HRRT camera based on LSO scintillation crystals and the phoswich concept; (B) the GSO-based PET (G-PET) camera; (C) the Hamamatsu SHR-12,000 PET scanner based on BGO detector pages; (D) the jPET-D4 brain PET scanner; (E) the NeuroPET; and (F) the PET-Hat wearable PET system. (Reproduced with permission from Zaidi et al.152) (Color version of figure is available online.)

tween the actual and perceived positions. The disadvantages are not insurmountable limitations, but can be improved upon, ie, parallax error can be halved by the phoswich approach that decreases the uncertainty of the DOI. The initial design of a positron device was undertaken at the Physics Research Laboratory at Massachusetts General Hospital with 2 opposing sodium iodide detectors as a trial for tumor localization in the brain in 1950. This was followed in 1952 with development of a clinical PET device that not only provided a coincidence scan but also an “unbalance scan” to help in tumor identification and lateralization.91 Next came the PC-I in the late 1960s and early 1970s, which allowed for better imaging characteristics that were further refined in PC-II. In the early to mid-1970s, Ter-Pogossian et al92 developed positron emission transaxial tomography (PETT) with an array of 24 NaI (Tl) crystals with coincidence imaging, attenuation correction, and appropriate filtered backprojection. PETT was refined in successive models to include rotation and more NaI(Tl) crystals to improve efficiency. Some of the PETT models even used an array of cesium fluoride crystals, which were denser than NaI with a shorter decay time but had very low light output.93-95 The initial PETT was tested in animal studies with 11C, 15O, and 13N for evaluation of blood flow and metabolism; acquired images were of adequate quality to measure physiological processes.96 However, PETT was limited by its field of view (20 cm) and use of positron emitters with short half lives requiring an on-site cyclotron. Human brain studies in which investigators used PET III showed ammonia distribution in the white and gray matter corresponding to normal blood flow to the former areas. In addition, the ammonia study showed intense uptake in malignant brain lesions and decreased uptake corresponding to areas of stroke. PET III was used also in conjugation with 11C in identifying large vessel versus capillary abnormalities

when combined with the ammonia studies. An example would be a stroke patient imaged with PET III showing a larger defect on 11C images compared with the ammonia images, supporting the localization of 11C to the larger vessels and ammonia to the smaller capillaries.97 In the footsteps of PET III, emission computer axial tomography (ECAT II) was developed with 66 NaI (Tl) detectors and was the first commercially available PET scanner. ECAT II intended to surpass PET III’s foundation with high resolution and contrast while providing for image sampling flexibility in multiple modes. Its redundant sampling allowed multiple detectors to sample the same point multiple times, which reduces the errors inherent with motion. For example, respective resolutions for head scans would be 1.3 cm for high resolution, 1.6 cm for medium resolution, and 2.2 cm for a low resolution scan.98 However, only the peripheral cortical uptake was visualized and anatomic details of specific structures could not be appreciated. Until the mid to late 1970s, the most common detector in usage was NaI (Tl); however, its low density limited its efficiency, scatter limited its spatial resolution, and it was difficult to produce because of hygroscopic nature. One scintillator crystal that showed promise was bismuth germinate (BGO) with its high density, similar decay constant to NaI(Tl), and its nonhygroscopic nature. The requirements of spatial resolution and efficiency limited the thickness of NaI (Tl) detectors to 2 cm but 6-7 mm BGO detectors could be built with improved resolution and greater efficiency. BGO has its disadvantages as well such as low light output and timing performance. On the principles of BGO, Thompson and colleagues99 developed POSITOME II with a 64 detector BGO ring to improve imaging characteristics. It was initially used in approximately 300 patients with brain tumors, strokes, and transient ischemic attacks who underwent positron scans with 77Kr and 68Ga.

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214 The first commercially available BGO camera was the NeuroECAT,100 which attempted to improve on the ECAT II’s resolution and sensitivity with 88 BGO detectors on each of the 3 detector arrays (Fig. 5). Additional BGO positron cameras were developed, including Positologica,101 neuroPET,102 HEADTOME III,36 Scanditronix PC-384,103 and PC2048-15B.104 The progress in the BGO cameras also helped delineate structures, such as the thalamus, caudate nuclei, and putamen, thereby adding anatomic detail to functional imaging. The mid to late 1980s also saw the development of block detectors in which the crystals and PMTs could be configured in various arrangements to better achieve high resolution and efficiency. The 1990s saw further refinement of PET cameras that would have brain applications, such as POSICAM 6.5105 and ECAT EXACT HR106 in addition to the cameras developed by Cho and colleagues.107,108 The early 1990s saw the advent of the Hamamatsu SHR 1200, which was unique in its patient-positioning capabilities. The patient could be imaged supine or sitting, allowing assessment of brain function in relation to its spatial position in space. It had a 5-ring BGO geometry (240 crystals/ring) with a resolution of ⬍4 mm in transaxial plane and ⬍6 mm in the axial direction and was capable of acquiring 9 simultaneous slice images.109 This model was further developed into the Hamamatsu SHR 12,000 in 2001, with a 24-ring geometry containing 11,520 crystals of BGO with the addition of updated and smaller photomultiplier tubes, an expanded field of view (FOV) at 163 mm and a spatial resolution of 2.9 mm in both the transaxial and axial directions. It also allowed for imaging in standing postures in addition to supine and sitting, providing for additional data input regarding positioning.110 The 1990s also saw the development of lutetium oxyorthosilicate (LSO) detectors, which are denser with significantly greater light output and faster decay times allowing for smaller crystal sizes and tighter geometry resulting in higher sensitivity, and resolution and decreased random events. This allowed for even more detailed imaging than had been previously achieved with the BGO cameras. The first such brain tomograph camera called the high-resolution research tomography (HRRT) consisted of approximately 120,000 LSO crystals with a uniform resolution of approximately 2.5 mm.111 High-resolution research tomography consists of 8 octagonally configured detector heads with DOI information, allowing for pulse shape discrimination to ascertain the site of event interaction (Fig. 6). It has 2 layers of LSO crystals, a large FOV, a 35-cm gantry opening, operates in 3-D mode, and has a spatial resolution of approximately 2.5 mm.112 In 1994, Head PENN PET was developed at University of Pennsylvania with a single annular NaI (TI) detector. It produces images in 3D (no intersepta) and uses Anger logic with large PMTs. It has very good spatial resolution with decreased scatter and random events because of energy resolution. Because it is a continuous detector, it eliminates the possibility of gaps in data seen with adjacent detectors. However, it has its drawbacks, such as pulse pile-up resulting in greater dead time and difficulty handling greater activity levels.113,114

Figure 7 Drawing and photograph of integrated MR/PET design showing isocentric layering of MR head coil, PET detector ring, and MR magnet tunnel (left). Simultaneously acquired MR, PET, and fused combined MRI/PET images of a 66-year-old man after intravenous injection of 370 MBq of FDG. Tracer distribution was recorded for 20 minutes at steady state after 120 minutes (right). (Originally from Schlemmer et al151 and adapted by Zaidi et al.152 Reprinted with permission.)

The University of Pennsylvania group also developed the G-PET in 2003 to address some of the issues with the Head PENN PET. It used 18,560 Gd2SiO5 (GSO) crystals in a hexagonal arrangement and has similar spatial resolution, slightly greater sensitivity; most importantly it differentiates itself from the prior camera with greater counting rates resulting in better imaging of dynamic physiological processes.115 The last few years have seen the development of jPET-D4 in Japan with 5 rings of 24 detector blocks each consisting of GSO crystals with 4 layers of DOI detectors. DOI detectors allow a larger solid angle coverage improving sensitivity, allow event localization in 3 dimensions and reduce degradation.116-118 More recently in 2009 a PET-HAT system was developed to assess functional brain properties in which fMRI would not be helpful. The system is small, inexpensive, and consists of a GSO block, DOI, and a tapered light guide. It has a transaxial and axial resolution of 4.9 mm full width at half maximum and 3.5 mm full width at half maximum at the center of FOV.119 In 2009, photodetection systems also introduced the NeuroPET, which is compact, easily movable, can use low doses for high quality of images and allows for longitudinal studies to be undertaken in a patient. It has 7680 crystals of CsI (Na), a gantry aperture of 31 cm and a transverse resolution of 2.9 mm and axial resolution of 5.0 mm at 1 cm.120

Clinical Applications of PET in Brain In addition to the PET applications already discussed earlier in the clinical applications section, PET has come a long way from its initial application for regional localization of tumor to the current cutting edge molecular imaging with novel

Evolution of brain imaging instrumentation tracers to elucidate disease processes, such as AD, Parkinson’s, and neuropsychiatric disorders, and to evaluate the effectiveness of treatment. Initially, PET served to localize regions in brain to function; however, our lack of understanding of complicated processes in the brain and the limited resolution of PET hampered further evaluation. PET studies investigating cerebral blood flow, rates of oxygen metabolism, and glucose use have helped our understanding of the physiological processes involved in the evolution of a stroke. In addition, investigators have shown prognostic and predictive value of PET in patients with carotid occlusion and stroke events.121,122 Parkinson’s disease involves derangements in the dopaminergic system and targeted imaging involving it have served to shed light on the pathogenesis of the disease process, whether it be presynaptic changes, changes in regulation of dopamine synthesis and transport or increased synaptic dopamine turnover.123-129 PET imaging has also been used to assess the effectiveness of treatment modalities, such as fetal tissue transplantation.130,131 AD represents most dementia cases and is likely to occupy a significant portion of future health care resources (whether it be financial or in human resources) as “baby boomers” age and people are living longer. In addition to the understanding of the AD process, PET has contributed to early identification of disease, allowing patients’ treatment regimens to then be initiated. Various PET tracers have been targeted to specific ligands, such as amyloid, ␶-protein, and microglia related to dementia. An example would be 2-[1-(6-[(2-18Ffluro-ethyl) (methyl) amino]-2-naphthyl) ethylidene] malononitrile which targets amyloid and shows characteristic changes in the temporoparietal and frontal lobes of patients with AD.132 In addition, Pittsburgh compound B, which has high affinity for amyloid plaques, has been studied and shown to have good correlation with amyloid plaque burden.133-137 Additional 18F compounds, such as 18F-florbetaben and (E)-4-[2-(6-[2-(2-(2-18Ffluoroethoxy) ethoxy) ethoxy] pyridine-3-yl) vinyl]-N-methyl benzeneamine, are promising as PET amyloid imaging tracers.138-140 Microglial targeting via benzodiazepine receptors with tracers, such as 11C-labeled N-(2,5-dimethoxybenzyl)-N-(5-fluoro-2-phenoxyphenyl)-acetamide, showed high levels of binding in patients with AD.141 PET has also made contributions to the field of neuropsychiatry in helping analyze biochemical abnormalities in the serotonergic and dopaminergic pathways.142-144

Dedicated CT or MRI and Hybrid PET/MRI Currently, the advances in CT and MRI, (especially fMRI) have made them the primary devices for diagnosis, prognosis, and determination of response to therapies. This is unique to the United States compared with Europe and Asia, where brain PET devices are used more in medical diagnosis and treatment. The limited soft-tissue specificity of CT hinders its role in brain imaging and explains why even though combined PET/CT units have now been available for many

215 years they are not extensively used for this purpose. MRI imaging offers greater anatomic detail and has no radiotracer injection, no ionizing radiation, short acquisition time, and very high resolution (1.5 mm ⫻ 1.5 mm) compared with PET. With the addition of fMRI, it can dynamically evaluate changes in blood flow assessing differential activation of various centers in the brain by oxygenated or deoxygenated status of hemoglobin. fMRI also extends the traditional role of MRI from exquisite anatomic details to include functional information about the brain with wider availability. Combining a PET and MRI holds great promise where the hybrid would be better than each standalone unit, allowing for simultaneous structural and functional data acquisition for medical diagnosis and treatment. Limitations to overcome before such a device can be put into clinical practice would be to address the artifacts that can be created by PET instrumentation in the MRI image, complications in attenuation correction, longer scan times (MRI acquisition is longer than CT), effects of the strong magnetic fields on PET instrumentation and cost. Extensive research has been undertaken in this area with prototype models under test with 4 possible designs. The ideal and first solution would be to do simultaneous PET and MRI acquisition, the second would be do sequential PET and MRI, the third would be to insert the PET between the magnets of MRI, and the fourth would be a PET insert between the radiofrequency coil and gradient set of the MRI (Fig. 7).145-152 Only time and further research will clarify the extent of the clinical contribution any of these systems would make to the arena of brain imaging.

Conclusions The anatomic detail provided by CT and MRI have caused them to be the primary imaging modalities of choice in evaluation of the brain. However, SPECT and PET imaging are still of great value but often underappreciated. The thrust towards greater molecular imaging has given arise to multiple specific targeted radiotracers to study the physiological processes of the brain, including neurotransmitter receptor imaging and tracers to evaluate response of neuropsychiatric drugs to name a few. PET is also valuable in assessing blood flood, oxygen and glucose metabolism to create a functional map of the brain. It is very helpful in evaluating patients in early stages of dementias where functional abnormality has not translated into a structural abnormality. In addition, the prospect of hybrid clinical imaging holds great promise in our further understanding of the brain with the combination of anatomic and functional data.

Acknowledgments We are deeply indebted to Dr Joseph Glaser, at Montefiore Medical Center, for his assistance in preparation of the manuscript.

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