Positron-emitting radionuclides are generated in a cyclotron. In this machine, charged particles (protons, deuterons, or negative hydrogen ions) are accelerated in a circular path to achieve sufficient kinetic energy. The particles are then directed to bombard a stable isotope and the resultant interaction creates a new, unstable, proton-rich isotope. This isotope becomes a more stable atom by a nuclear process in which a proton is converted to a neutron, a positron (the antiparticle of the electron with the same mass but positively charged), and a neutrino. The positron and neutrino are emitted from the nucleus of the radioactive species at a characteristic decay rate, depending on the particular isotope. The positron-emitting isotopes most often produced for PET studies are radioactive forms of oxygen (¹⁵O), nitrogen (¹³N), carbon (¹¹C), and fluorine (¹⁸F). These isotopes have decay rates in the range of minutes to hours (e.g., half-lives of 2 minutes for ¹⁵O and 109 minutes for ¹⁸F) and are ideally suited for biologic imaging because there is sufficient time to image their presence in the body without producing long-term radiation exposure (see Table 20-1 for the physical characteristics of radioisotopes). These radioisotopes can be readily incorporated into a wide variety of molecules, including the labeling of physiologic substrates (e.g., glucose, amino acids), neuroreceptor ligands, and substrates and inhibitors of enzymes. The injectable end product is then introduced into the body, usually by intravenous injection. Because these compounds are injected in minute quantities (subnanomolar concentrations) and do not produce pharmacologic effects, they are referred to as biologic tracers or probes. The tracer is then distributed throughout the body in accordance with its delivery, uptake, and metabolism characteristics. Throughout this time, the tracer continues to decay and emit positrons and neutrinos. The neutrinos pass through the body and are not detected. Wherever the tracer is trapped in tissues, the positrons travel only a short distance (≈1 mm) and lose energy in collisions with electrons in the tissue, until they collide with nearby electrons, which results in annihilation of the two particles and conversion of their masses into two gamma-ray photons, referred to as annihilation photons. These photons each have an energy of 511 keV and are projected linearly at approximately 180 degrees to each other. They have a high probability of escaping the body without attenuation, which allows their detection. A pair of detectors set at 180 degrees to each other can register the arrival of these photons and localize the positron emitter along that line of travel, referred to as a coincidence line, or line of response. For a given localized concentration of positron emitters, the resultant photon pairs are emitted in all directions and can be detected by a circumferential ring of scintillation detectors (Fig. 20-1). On combining the lines of response from many different angles, the data are reconstructed with a mathematical algorithm (special coincidence technique called a reconstruction algorithm) to establish their distribution pattern, a pattern that corresponds to regional concentrations of the radionuclide. These profiles are then used to produce tomographic brain images, which can then be coregistered with computed tomography (CT) or magnetic resonance imaging (MRI) to obtain precise anatomic localization.⁶

TABLE 20-1 Physical Properties of Selected Positron-Emitting Radionuclides

RADIONUCLIDE	HALF-LIFE	MAXIMAL POSITRON ENERGY (MeV)
¹⁸F	109.7 min	0.64
¹¹C	20.4 min	0.96
¹³N	9.96 min	1.19
¹⁵O	2.07 min	1.72
²²Na	2.6 yr	0.55
⁶⁴Cu	9.7 min	0.65
⁶⁸Ga	67.6 min	1.89

FIGURE 20-1 The positron-electron interaction results in their annihilation and the coincident emission of two 511-keV photons at 180 degrees to each other. Detection of the essentially simultaneous arrival of these annihilation photons at the positron emission tomography camera detectors establishes a coincidence line (line of response). In an actual tomogram that registers the photons emitted from regions of accumulated radioactivity, there are about 1 to 2 million detector pair combinations that can record these events simultaneously. For a subject injected with [¹⁸F]fluoro-2-deoxy-D-glucose (FDG), the distribution and accumulation of radioactivity throughout the entire body can be imaged by sequentially moving the subject through the ring of detectors. The darker areas represent regions of higher glucose metabolic rates.

(Adapted from Phelps ME. PET: The merging of biology and imaging into molecular imaging. J Nucl Med. 2000;41:661-681.)

For a PET brain study, the tracer, on injection, is distributed and accumulated in tissues as a function of time. Accordingly, different time intervals of data acquisition (frames) are used to discriminate these time-dependent changes in regional concentrations of activity. Immediately after injection of the tracer, short time frames of 1 minute or less are acquired to image the rapid changes in radioactivity, whereas at later times, longer time frames of 5 to 10 minutes suffice. These temporal and spatial distributions of radioactivity are then fitted to a kinetic model that has been designed to quantify the biologic process being investigated.

Camera and Brain Imaging

The PET camera is a sophisticated imaging instrument that is used to measure the photons generated from positron-electron annihilation. The PET camera can acquire data in intervals that range from seconds to minutes, thereby allowing monitoring of many biologic processes. The quality and quantity of the acquired data from a particular PET camera are a function of technical parameters, some of which are described later. These parameters are often listed in the methods sections of PET studies because they provide critical information on the quality of the data acquisition.

Sensitivity refers to the fraction of positron emission events within a field of view that is detected by the camera. As the relative sensitivity of a camera increases, more counts from the same amount of radioactivity are detected, which results in an increase in the signal-to-noise ratio and therefore better image quality.

Spatial resolution, or the ability to accurately locate events, refers to the smallest distance between two points that can be distinguished by the PET scanner. This parameter defines the ability of the camera to differentiate spatial activity and is based primarily on the camera detector elements, with smaller elements providing better detail. A typical clinical PET camera has a spatial resolution of 5 to 8 mm; small animal scanners have a resolution as low as 2 mm.⁷ With recent advances in detector and scanner design technology, the sensitivity and spatial resolution of PET have dramatically improved, especially as data collection has evolved from a two- to a three-dimensional mode of acquisition (which increases the number of gamma rays being collected). State-of-the-art PET cameras can now image subregional cortical and subcortical structures throughout the brain (Fig. 20-2).

FIGURE 20-2 [¹⁸F]Fluoro-2-deoxy-D-glucose (FDG) and positron emission tomography (PET)–computed tomography (CT) imaging. Left, The two columns show the tomographic planes of sagittal (column 1) and transaxial (column 2) CT data (top row) and the PET data overlaid on the CT images (bottom). Right, Transaxial planes of FDG-PET images covering the superior to inferior extent of the brain. The darker areas represent regions of higher glucose metabolic rates and clearly delineate cortical and subcortical structures.

(Courtesy of D. H. Silverman, M.D., Ph.D., Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles.)

Full width at half-maximum (FWHM) is a technical term that refers to the width of a gaussian-shaped curve at half its maximal peak value. When activity is acquired from a single point source, the PET camera has a limited ability to accurately locate that activity, which results in a spatial distribution of that activity that resembles a bell-shaped curve. The corresponding FWHM for that distribution is used to define the spatial resolution of the PET camera (i.e., objects that are closer together than one FWHM cannot be distinguished).

Partial volume correction describes methods for removing errors in the regional quantification of activity caused by analysis of regions that are smaller in width than twice the spatial resolution of the camera (i.e., regions with a diameter less than two times the FWHM). For example, if the FWHM is expressed as 4 to 5 mm, any structure less than 10 mm will be affected by concentrations of radioactivity in the surrounding areas. If the structure of interest has a higher concentration than adjacent structures, its concentration of radioactivity will be underestimated. In contrast, if the structure of interest has a lower concentration than adjacent structures, its radioactivity will be overestimated. In general, a region of interest should be quantified only when its size is twice that of the FWHM. Therefore, whenever a small region of interest is quantified, its dimensions should be stated relative to the spatial resolution of the camera. However, further processing of the data can correct for this partial volume effect, provided that the spatial resolution of the PET camera, the exact size and shape of the region, and the relative concentrations of radioactivity are all known. The methods of partial volume correction that have been developed require an MRI scan or other anatomic brain image of the individual.⁸

Image reconstruction refers to the mathematical process of creating an image from a series of detection events obtained from the PET camera. Radioactive decay events are detected as lines of response, and a reconstruction algorithm is used to determine the distribution of radioactivity from the summation of all observed lines of response. The most commonly used reconstruction algorithm initially was called filtered backprojection (FBP). With FBP, the counts from all detector pairs are projected back along the lines of response where they originated, which results in overlapping of backprojections and a corresponding two-dimensional distribution of emission origins. Before projection, these data are processed with a mathematical filter algorithm, relatively graded from sharp to smooth, to improve the signal characteristics. Sharp filters result in better spatial resolution and more statistical noise, whereas smooth filters result in less resolution and a reduction in statistical noise.⁹ The FBP method is increasingly being replaced by iterative reconstruction methods (e.g., maximal likelihood estimation) that essentially begin with an estimated image based on the intersection of lines of response followed by comparison of its calculated projection data with the actual projection data. With subsequent iterations, the image is revised until convergence is achieved, with limiting factors being the technical features of the detector system.

Tracer Kinetic Models

Hundreds of PET tracers have been synthesized for research in animal and human imaging studies. A representative list of positron-labeled compounds is presented in Table 20-2 to illustrate the wide range of imaging applications. It should be emphasized that the initial PET data acquisition reflects the total radioactivity in a region over the time that the data were acquired. Because only radioactivity is measured in the brain and not the relative concentrations of the tracer and its metabolites, optimal use of a particular PET tracer requires an appropriate tracer kinetic model to interpret the observed changes in radioactivity levels. Tracer kinetic models provide a mathematical framework by which the time course of tracer distribution and changes in regional concentrations of accumulated radioactivity are used to derive rates of biologic processes.

TABLE 20-2 Examples of Radiolabeled Compounds Used for Positron Emission Tomography

LABELED COMPOUNDS	PRIMARY APPLICATION
Physiology
H₂¹⁵O, C¹⁵O₂	Blood flow
¹¹CO, C¹⁵O, ⁶⁸Ga-EDTA	Blood volume
3-(O-[¹¹C]methyl)-D-glucose	Glucose transport
Metabolism, Biosynthesis, Transport
2-[¹⁸F]Fluoro-2-deoxy-D-glucose	Glucose metabolic rates
[¹¹C]Palmitic acid	Free fatty acid metabolism
[¹³N]Glutamate, [¹³N]alanine	Transaminase activity
[¹¹C]Acetate	Krebs cycle function
¹⁵O₂	Oxygen utilization
L-1-[¹¹C]Leucine, L-1-[¹¹C]valine	Protein synthesis
L-1-[¹¹C]Tyrosine, L-1-[¹¹C]phenylalanine, 6-[¹⁸F]fluoro-L-dopa, 2-[¹⁸F]fluorotyrosine, [¹¹C]methyl-L-methionine	Brain tumors
[¹¹C]Thymidine	DNA replication (cell growth)
[¹⁸F]Fluoride	Bone cell growth
[¹¹C]Verapamil	P-glycoprotein

NEURORECEPTORS	RECEPTOR TYPE
[¹⁸F]SCH 23390, [¹¹C]SCH 23390, [¹¹C]NNC 112	D₁
[¹¹C]Raclopride, [¹⁸F]fluoroethylspiperone, [¹⁸F]fallypride	D₂
[¹⁸F]MPPF	5-HT_1A
[¹⁸F]Altanserin	5-HT_2A
6-[¹⁸F]Fluoro-A-85380	Nicotinic
[¹¹C]Carfentanil, [¹¹C]diprenorphine	Opioid
[¹¹C]Flunitrazepam	Benzodiazepine
[¹¹C]Flumazenil	Benzodiazepine/epilepsy
N-Methyl-[¹¹C]PK 11195	Benzodiazepine/glia
[¹¹C]Scopolamine	Muscarinic
Neurotransmitter Biochemistry
6-[¹⁸F]Fluoro-L-dopa, 4-[¹⁸F]fluoro-m-tyrosine	Dopamine synthesis
[¹¹C]WIN 35,428, [¹⁸F]FPCIT	Dopamine transporter
[¹¹C] McN5652, [¹¹C]DASB	Serotonin transporter
[¹¹C]Dihydrotetrabenazine	Vesicular monoamine transporter
[¹¹C]Ephedrine, [¹⁸F]fluorometaraminol, 6-[¹⁸F]fluorodopamine	Adrenergic terminals
Enzyme Probes
5-[¹⁸F]Fluoro-2′-deoxyuracil	Thymidylate synthetase
[¹¹C]Deprenyl	Monoamine oxidase

EDTA, ethylenediaminetetraacetic acid.

To construct kinetic models, the biologic process is categorized into compartments (e.g., plasma and a tissue region would represent a two-compartment model) and then formulated by differential equations that describe exchange of the isotope between compartments.¹⁰ In general, models contain parameters that are used to determine transport rates of the tracer into and out of the region of interest, the extent of tracer-receptor binding, and enzymatic activities. The images that are constructed from these parameters and subsequent model fitting are referred to as parametric images.

A typical three-compartment tracer kinetic model is presented in Figure 20-3. After intravenous injection of the tracer, the time course of the tracer concentration in plasma (obtained from arterial blood samples) is determined. This plasma-time activity curve is referred to as the input function and is used to provide a quantitative parameter on tracer availability to the brain as a function of time.

FIGURE 20-3 A, Three-compartment tracer kinetic model for [¹⁸F]fluoro-2-deoxy-D-glucose (FDG) that consists of plasma, tissue free FDG, and trapped FDG-6-phosphate (FDG-6-P) compartments. The FDG is transported from plasma to the tissue. The subsequent phosphorylation rate, k₃, is proportional to the use of glucose by the tissue. The K₁ rate coefficient (milliliters per minute per gram) accounts for blood flow and tracer extraction; the fractional rate constants (k₂, k₄) each represent the fraction of the tracer that leaves the respective compartment per unit time. B, On phosphorylation, glucose-6-P continues through the glycolysis pathway, but FDG-6-P is not a substrate for further metabolism and remains trapped within the tissue.

(From Phelps ME, Mazziotta JC, Heinrich R, et al. Positron Emission Tomography and Autoradiography: Principles and Applications for the Brain and Heart. New York: Raven Press; 1986.)

The time course of tracer activity in the brain is obtained from the PET measurements. A tracer kinetic model can then be used to calculate rate constants for exchange of the tracer between compartments. The following is a description of the model used for monitoring metabolic rates of glucose in the brain.

2-[¹⁸F]Fluoro-2-deoxy-D-glucose (FDG) is the most widely used tracer in PET studies. It was adapted from the 2-deoxyglucose (2-DG) method for imaging glycolysis by autoradiography as developed by Sokoloff.¹¹^,¹² The 2-DG method established that measurement of 2-DG accumulation could be used to quantify metabolic rates of glucose, which are closely coupled to functional activity of the brain (e.g., increased glucose consumption with focal seizures, decreased glucose consumption with anesthesia or blockade of visual input).

FDG is a fluorinated analogue of 2-DG, and its use in PET is a direct extension of Sokoloff’s model. In the brain, FDG is used to measure the cerebral metabolic rate of glucose (CMRGlu) in selected regions. FDG and glucose are transported by the same carrier across the blood-brain barrier into tissues (see Fig. 20-3). Both compounds then enter the glycolysis cycle and are phosphorylated by the enzyme hexokinase. However, after this step, FDG-6-phosphate, unlike glucose-6-phosphate, is not a substrate for further metabolism, and it remains trapped in the tissue for at least 1 hour before slowly leaving the tissue. Accordingly, FDG-6-phosphate accumulates in the tissue proportional to that tissue’s metabolic rate of glucose. To correct for small relative differences between FDG and glucose as substrates for hexokinase activity, an additional factor—the “lumped” constant—is used in calculating the metabolic rate of glucose.

The FDG compartmental model contains rate constants as the kinetic parameters used to assess the transport and phosphorylation of FDG. Based on this model using FDG, CMRGlu can be obtained from the following equation:

where Cp is the plasma glucose concentration and LC is the lumped constant. The parameter K₁ is a rate coefficient (mL/min/g) that represents the transport of FDG from plasma to tissue and accounts for blood flow and extraction of tracer. First-order rate constants (min⁻¹) represent the transport of FDG from tissue to plasma (k₂) and phosphorylation of FDG to FDG-6-phosphate by hexokinase (k₃); a correction factor (k₄) can be added to account for the small amount of dephosphorylation of FDG-6-phosphate that can occur at later times (60 to 90 minutes after injection).

Positron Emission Tomography for the Assessment of Biologic Disease Processes in the Brain

PET imaging provides an in vivo characterization of biologic processes at the neurochemical level. A variety of substrates, substrate analogues, and drugs have been synthesized for tracer assays of different components of the neurotransmitter pathways. With these tracers, noninvasive imaging of the brain can be used to detect the presymptomatic phase of a disease process, monitor disease progression, assess the efficacy of therapy, and evaluate neuroprotective and neurorestorative interventions. The following studies of movement disorders, dementias, epilepsy, brain tumors, stroke, and head injury represent ongoing clinical research in which PET is used to reveal new insights into brain dysfunction.

Detection and Diagnosis of Neurological Dysfunction

Movement Disorders

A wide range of movement disorders associated with basal ganglia dysfunction have been imaged with PET. Neurochemical deficits have been identified that uniquely characterize Parkinson’s disease, Huntington’s disease, progressive supranuclear palsy, multiple system atrophy, essential tremor, and dystonia. In particular, striatal dopamine system abnormalities have been studied with tracers specifically designed to assess different components of presynaptic and postsynaptic function.¹³ For example, dopamine synthesis capacity is used as an index of presynaptic terminal functional integrity, whereas binding of tracer to the dopamine transporter (DAT) is used to estimate nerve terminal density. For the postsynaptic system, ligands that bind to dopamine receptors have provided measures of receptor number (B_max) and receptor affinity (K_d).¹⁴^,¹⁵ The opportunity to conduct longitudinal studies with these tracers provides a unique noninvasive methodology for monitoring the temporal progression of many disease processes.¹⁶ The use of PET to assess nigrostriatal deficits in Parkinson’s disease and the striatal degeneration associated with Huntington’s disease is discussed next.

Parkinson’s Disease

The progressive loss of nigrostriatal neurons eventually exceeds a nonsymptomatic threshold, at which point motor and cognitive symptoms appear.¹⁷^,¹⁸ However, even before symptoms begin, underlying deficits in the dopamine system can be detected with PET. The capability of detecting these biochemical deficits in the striatal dopamine system can provide insight into the differential diagnosis and therapeutic options.

The first approach to imaging presynaptic integrity of the dopamine system in patients with Parkinson’s disease was based on the assessment of striatal dopamine synthesis capacity.¹⁹ The clinical application of exogenous L-dopa as a substrate for brain dopamine synthesis provided the rationale to synthesize a fluorinated analogue of L-DOPA, [¹⁸F]6-fluoro-L-dopa (FDOPA), as a PET tracer. FDOPA is transported across the blood-brain barrier into the brain by the large neutral amino acid transporter, as is L-DOPA and other large neutral amino acids.²⁰ In dopaminergic presynaptic terminals, FDOPA is a substrate for aromatic amino acid decarboxylase and is converted to [¹⁸F]fluorodopamine (FDA), which is subsequently stored in vesicles. The extent of FDA accumulation in striatum during the imaging period is used to estimate dopamine synthesis rates.²¹ Thus, reductions in FDA accumulation in patients with Parkinson’s disease have been associated with decreases in dopaminergic terminal activity. Moreover, relative decreases in accumulation of FDA between the caudate and putamen, as well as between putaminal subregions, have been used to stage progression of Parkinson’s disease (Fig. 20-4).

FIGURE 20-4 Noninvasive imaging of early Parkinson’s disease. The magnetic resonance image (A) of the striatum does not indicate any significant anatomic abnormalities, but positron emission tomography (PET) reveals regional and selective alterations in neurochemical processes. The [¹⁸F]fluoro-2-deoxy-D-glucose–PET image (B) shows abnormal putamen hypermetabolism (≈10%) relative to the caudate. The [¹⁸F]fluoroethylspiperone–D₂ receptor binding image (C) shows regional densities in the putamen that are about 15% greater than those in the caudate. The dopamine synthesis–[¹⁸F]6-fluoro-L-DOPA uptake image (D) shows a significant reduction in dopamine synthetic capacity (80%) in the putamen but not in the caudate. Arrows in B, C, and D indicate putamen.

(From Phelps ME. PET: The merging of biology and imaging into molecular imaging. J Nucl Med. 2000;41:661-681.)

Additionally, FDG has been used in conjunction with FDOPA to provide a complementary assessment of compensatory regional alterations in glucose metabolism.²² These PET assessments have been used to differentiate idiopathic Parkinson’s disease from related movement disorders.

An alternative to FDOPA assessment of striatal dopamine system integrity is obtained with PET tracers that bind selectively to the presynaptic DAT and thereby may provide an index of its terminal density.²³ For example, the cocaine congener N-(3-¹⁸F-fluoropropyl)-2β-carbomethoxy-3β-(4-iodophenyl)nortropane ([¹⁸F]FPCIT), which has high binding affinity for the DAT (Fig. 20-5), has been used to show how the pathology in Parkinson’s disease progresses from unilateral to bilateral striatal dopamine deficits and that their magnitude correlates with the severity of behavioral symptoms.²⁴ Other [¹⁸F]FPCIT-PET studies have revealed 50% decreases in mean striatal DAT binding in patients with early-stage Parkinson’s disease who were imaged within 2 years of diagnosis, thus suggesting that significant nigrostriatal degeneration had occurred by the time that the first symptom appeared.²⁵

FIGURE 20-5 Progression of striatal dopamine system degeneration in Parkinson’s disease (PD). The dopamine transporter (DAT) is located at the presynaptic terminal, and its density in the striatum can be used as an index of dopamine system integrity. The positron emission tomographic images show the striatal uptake of N-(3-¹⁸F-fluoropropyl)-2β-carbomethoxy-3β-(4-iodophenyl)nortropane ([¹⁸F]FPCIT), a ligand with high binding affinity for DAT, for a normal volunteer (top row) and two patients with PD (middle row: Hoehn & Yahr (H&Y) stage I; bottom row: H&Y stage III). [¹⁸F]FPCIT uptake is reduced predominantly in the putamen, unilaterally in early-stage PD (middle row) and more pronounced bilaterally (bottom row) with disease progression.

(From Kazumata K, Dhawan V, Chaly T, et al. Dopamine transporter imaging with fluorine-18-FPCIT and PET. J Nucl Med. 1998;39:1521-1530.)

For the postsynaptic striatal dopamine system, PET tracers have been synthesized for the dopamine D₁ and D₂ receptors.²⁶ These receptors subserve different functions based on their signal transduction mechanisms of stimulation and inhibition of adenylyl cyclase, respectively.²⁷ At present, PET studies of dopamine receptors have been limited to the assessment of receptor density and, in some instances, receptor affinity.

Nonetheless, changes in apparent ligand-receptor binding are indicative of dysfunctional neurotransmission at the synapse. For example, changes in D₂ receptor density in patients with Parkinson’s disease as a result of compensatory reactions to the ongoing disease process have been measured with PET.²⁸ Subregional striatal alterations that show larger increases in D₂ receptor binding in the putamen than in the caudate have also been detected (see Fig. 20-4). These relative differences in receptor density are paralleled by a similar pattern of increases in FDG metabolism; that is, metabolic rates in the putamen are greater than those in the caudate.

PET can also provide in vivo assessments of the efficacy of neurosurgical interventions. In the United States, two National Institutes of Health–sponsored double-blind trials were conducted in which fetal mesencephalon cells were transplanted into the striatum of patients with Parkinson’s disease.²⁹^,³⁰ Although clinical improvements appeared only marginal and the primary end points were not met, the integrity of the grafts to survive in the host striatum was unequivocally demonstrated with FDOPA–PET studies (Fig. 20-6). At present, novel neurorepair and neurorestoration strategies are being developed that include stereotactic delivery into the brain of neuronal growth factors (e.g., glial cell line–derived neurotrophic factor, genetically engineered viral vectors that deliver genes of interest, and stem cells). The long-term efficacy of these interventions will be assessed by PET.

FIGURE 20-6 [¹⁸F]6-Fluoro-L-dopa (FDOPA) imaging of fetal nigral cell transplantation into the striatum of patients with Parkinson’s disease. Longitudinal positron emission tomography studies show baseline putaminal deficits in FDOPA uptake in patients with Parkinson’s disease and subsequent striatal FDOPA increases at 1 and 2 years after fetal cell transplantation (top row: patient with one donor per side; middle row: patient with four donors per side). The sham/placebo patient (bottom row) shows further reductions in FDOPA uptake over the same time period, a finding suggesting disease progression.

(From Olanow CW, Goetz CG, Kordower JH, et al. A double-blind controlled trial of bilateral fetal nigral transplantation in Parkinson’s disease. Ann Neurol. 2003;54:403-414.)

Huntington’s Disease

The neurodegeneration associated with this autosomal dominantly inherited disease results in a significant loss of the medium spiny GABAergic (secreting γ-aminobutyric acid [GABA]) neurons of the striatum. Because these cells contain the majority of dopamine receptors in the striatum, a decrease in dopamine receptor binding accompanies their loss.³¹ Accordingly, changes in dopamine receptor binding were targeted for assessment with PET. Because striatal GABAergic neurons express D₁ and D₂ receptors, PET studies initially focused on alterations in these receptor densities by using the D₁ receptor ligand [¹¹C]SCH 23390 and the D₂ receptor ligand [¹¹C]raclopride. PET studies have shown that progression of Huntington’s disease is accompanied by significant reductions in both striatal D₁ and D₂ receptor binding.³¹

Additionally, FDG studies have shown that the striatum of carriers with asymptomatic Huntington’s disease mutations has reductions in FDG activity characteristic of the disease. These results are in contrast to the normal appearance of the same structures on MRI, thus illustrating that significant biochemical alterations are not necessarily paralleled by a similar degree of morphologic change.

Hence, detection by PET of asymptomatic disease and progression of Parkinson’s and Huntington’s disease demonstrates that biochemical reserves, redundancies, and compensatory responses can mask altered function up to a certain limit. Longitudinal assessment of these processes with PET now presents the opportunity to determine subsets of individuals who are likely to benefit from neuroprotective and neurorestorative therapies. As access to PET expands to the broader clinical community, medical evaluation will shift to such early detection—when, as these studies show, there is significant residual function that can become the target of intervention. In the future, neurosurgeons will increasingly rely on PET for planning of intervention treatments and assessment of outcomes.

Dementias and Mental Illness

Clinically, early dementia is difficult to differentiate from related pathologies associated with aging processes. Here, as with movement disorders, the goal of present and future research is to develop PET tracers that can be used for early diagnosis and assessment of the efficacy of therapy.

At present, FDG-PET can diagnose Alzheimer’s disease and distinguish it from patterns of normal aging.¹⁶ Specifically, hypometabolism can be detected in cortical neuronal pathways, which represents the summative effect of decreases in regional synaptic activity. These deficits are most prominent in the parietal and temporal lobes rather than the motor and visual cortex and become more marked and widespread with increasing disease severity.³²^,³³ Additionally, the hypometabolism is not generalized to subcortical structures such as the basal ganglia and thalamus.

It is now apparent that the major histopathologic aspects of Alzheimer’s disease, namely, amyloid plaques and neurofibrillary tangles, are present in brain before the onset of cognitive decline.³⁴^–³⁶ The predominant role hypothesized for β-amyloid in producing neuronal dysfunction has made it an attractive target for in vivo PET imaging, whereby disease progression and the efficacy of interventions designed to reduce the amyloid burden could be assessed. Recent advances in imaging amyloid in the brain have been achieved by using novel PET ligands that are modifications of histologic dyes with high binding affinity for amyloid. The most promising compound currently used for imaging amyloid is N-methyl-[¹¹C]2-(4′-methylaminophenyl)-6-hydroxybenzothiazole, also referred to as the Pittsburg-B Compound ([¹¹C]-PIB).³⁷ Patients with Alzheimer’s disease imaged with [¹¹C]-PIB show greater retention of [¹¹C]-PIB in cortical regions associated with accumulation of amyloid than in the pons or cerebellum, where there is little or no amyloid (Fig. 20-7). Multiple studies of Alzheimer’s disease patients with [¹¹C]-PIB and FDG imaging have now shown that the apparent amyloid burden remains relatively high and stable over a 2-year period while cerebral glucose metabolism continues to decline, thus suggesting that amyloid accumulation precedes the associated loss of cognitive function.³⁸

FIGURE 20-7 Imaging brain amyloid burden in patients with Alzheimer’s disease (AD). The positron emission tomography (PET) tracer N-methyl-[¹¹C]2-(4′-methylaminophenyl)-6-hydroxybenzothiazole, also referred to as [¹¹C]PIB, has high binding affinity for amyloid in vivo. [¹¹C]PIB-PET studies show that in frontal and temporoparietal brain regions known to contain amyloid there is significantly greater [¹¹C] retention in a patient with AD (right column) relative to a healthy control subject (left column); the standardized uptake value (SUV) represents the tissue concentration of tracer as measured by the PET scanner divided by the injected dose per kilogram of patient body weight. 2-[¹⁸F]Fluoro-2-deoxy-D-glucose (FDG) studies obtained within 3 days in a patient with AD show hypometabolism in the temporoparietal cortex (arrows; bottom right) and apparent preserved metabolic rate in the frontal cortex.

(From Klunk WE, Engler H, Nordberg A, et al. Imaging brain amyloid in Alzheimer’s disease with Pittsburgh Compound-B. Ann Neurol. 2004;55:306-319.)

PET has also contributed to refinement of the diagnosis and surgical treatment of mental illnesses such as severe major depression ³⁹ and obsessive-compulsive disorders.⁴⁰ A clinical response to antidepressants is associated with decreases in rates of glucose metabolism in the limbic (subgenual cingulate cortex, hippocampus, insula, and pallidum) and striatal regions, with increases in the dorsal cortical (prefrontal, parietal, anterior, and posterior cingulate) regions.⁴¹ Mayberg and colleagues used the findings of increased blood flow in the subgenual cingulate cortex to identify a target for deep brain stimulation to abate the symptoms of medically refractory major depression. Their early work demonstrated the integral role played by the subgenual cingulate cortex in both normal and pathologic shifts in mood.⁴² Increases in limbic and paralimbic blood flow, as measured with PET, occur in the subgenual cingulate cortex and anterior insula during sadness. Furthermore, there is a significant inverse correlation between blood flow in the subgenual cingulate cortex and the right dorsolateral prefrontal cortex.⁴³ In 2005, Mayberg and associates implanted deep brain stimulation electrodes into the bilateral subgenual cingulate cortex in six patients with medically refractory major depression. With stimulation, patients reported positive emotional phenomena.⁴⁴ In the acute postoperative period, the patients experienced reproducible increases in activity and mood scores that were not seen during sham stimulation. Chronic stimulation at high frequency probably resulted in reduced functional stimulation in the site. Subsequently, significant improvement in behavioral responses and remission of depression were observed in four of the six patients at 6 months. These well-conducted studies showed the effectiveness of PET in enhancing our knowledge of brain function and leading to effective diagnosis and therapeutic interventions.

Changes in FDG-PET patterns of cortical uptake in the frontal areas have also been demonstrated in patients with internal capsule lesions,⁴⁵ as well as with deep brain stimulation for the management of obsessive-compulsive disorder.⁴⁶ Thus, evidence is accumulating to support the use of PET for determination of targets and follow-up of patients undergoing neurosurgical interventions for mental illness.

Clinical Applications

Epilepsy

The outcome of epilepsy surgery is directly linked to accurate localization of the focus of the seizures. Improvements in techniques for localization of the seizure focus have resulted from advances in brain imaging. Currently, electroencephalography (EEG) is used to localize the focus, and imaging studies are used to corroborate the EEG findings. In the future, imaging studies will be incorporated into standard protocols for localization because of the high degree of accuracy of PET and volumetric MRI studies. This trend evolved from earlier findings with pneumoencephalography that demonstrated hippocampal atrophy, but modern imaging techniques can decrease the use of invasive EEG methods such as implantation of grids and depth electrodes.⁴⁷

FDG-PET scanning first demonstrated focal seizure abnormalities in the absence of structural changes.⁴⁸ Currently, single-photon emission computed tomography (SPECT), magnetoencephalography (MEG), and magnetic resonance spectroscopy (MRS) are also capable of showing abnormalities consistent with seizure foci in the absence of structural changes.⁴⁹ It is likely that these imaging modalities will provide complementary data for specific clinical situations. PET imaging with [¹¹C]flumazenil is also used to detect focal abnormalities. [¹¹C]Flumazenil is an antagonist with high binding affinity for the benzodiazepine site on GABA_A postsynaptic receptors. The region of the epileptogenic focus is localized by detecting a reduced area of [¹¹C]flumazenil binding, which can be overestimated as a larger area of hypometabolism when imaged with interictal FDG-PET.⁵⁰ The merits of PET are discussed in this section; other modalities are evaluated elsewhere in this volume.

Temporal Lobe Epilepsy

Temporal lobe epilepsy has been extensively studied with PET because of the prevalence of its surgical treatment.⁵¹^,⁵² At present, the process of resecting the seizure focus is divided into three phases. Phase I consists of noninvasive studies for localization of the seizure focus as defined by the semiology of the seizure, by scalp EEG findings, including needle electrodes (e.g., sphenoidal electrodes), and by imaging studies. Phase II is undertaken only if the phase I studies fail to localize the seizure focus. Phase II consists of invasive EEG studies, including electrocorticography with strips, grids, and depth electrodes implanted stereotactically. Because phase II studies substantially increase the morbidity of the surgical process, it is desirable to minimize their use.⁵³ Phase III is resection of the seizure focus.⁵⁴ Ideally, all the information necessary for characterization of the resection is obtained before the surgical procedure.

The need for accurate noninvasive localization becomes even more pressing for minimally invasive neurosurgery such as radiosurgery, which is now available for the treatment of focal epilepsy.⁵⁵ FDG-PET has been the most reliable imaging technique for lateralization of the seizure focus in temporal lobe epilepsy and for identification of cortical dysplasias, even when findings on MRI are unremarkable.⁵⁶^,⁵⁷ FDG-PET has provided detailed information on cell firing in minute foci, such as the origin of electrical discharges resulting in gelastic seizures in patients with hypothalamic hamartoma.⁵⁸ Radiosurgery directed to such hypermetabolic foci can lead to significant decreases in and even complete resolution of seizures.⁵⁹

The University of California, Los Angeles, group showed in a retrospective study of patients undergoing temporal lobe resection that the use of FDG-PET resulted in 86% sensitivity and 100% specificity for lateralization of the seizure focus.⁵³ This study demonstrated that localization was correct in all patients with glucose hypometabolism. Of the patients studied, only 14% of those undergoing resection did not have glucose hypometabolism in the resected lobe.⁵¹^,⁵² These results were reproduced in a study in which all patients with unilateral temporal lobe hypometabolism as assessed by FDG-PET had congruent results with invasive EEG studies.⁵⁷ Additionally, FDG-PET correlated with the semiology of the seizure. Patients with only aura and staring spells showed regional hypometabolism that was confined to the mesial temporal lobe structures, whereas patients with posturing as a component of their complex partial seizures had hypometabolism extending to the frontolateral cortex and motor cortex regions. Patients with complex automatism had hypometabolism in widespread areas, including the ipsilateral and contralateral limbic structures.⁴⁷ At present, neuronal loss in the seizure focus is the most plausible hypothesis for the interictal hypometabolism detected by FDG-PET. Although hypometabolic regions distant from the focus are also observed, these decreases may arise secondarily from diaschisis (see Fig. 20-10) as a result of primary loss of neurons in the region of the seizure focus.⁶⁰

MRI volumetric measurements of the hippocampus and amygdala also have high sensitivity and specificity in determining the seizure focus.⁶¹ T2 relaxometry denoting gliosis in the hippocampus offers additional information when MRI is used.⁶² When hippocampal atrophy is present, neuronal loss is highly predictable, especially in the CA1 subfield. Such characterization corresponds to FDG-PET–defined hypometabolism, and the PET results are more reliable than those obtained with T2 relaxometry.⁶³ The results of visual inspection, including volume and T2 relaxometry, reached a concordance of 90% with EEG lateralization; the addition of volumetric calculations generated with computer workstations brought this concordance to 97%. The congruency of EEG, MRI volumetric, and T2 relaxometric findings with FDG-PET hypometabolism is now considered sufficient for lateralization of the focus.

Further information on lateralization can be obtained with MRS.⁶⁴ MRS offers quantitative tissue spectra of N-acetylaspartate (NAA), choline, creatine, phosphocreatine, and lactate in the epileptic zone. NAA is found in neurons, whereas choline and creatine are found predominantly in glia. Therefore, relative decreases in NAA may represent neuronal loss, and increases in choline and creatine may denote gliosis.

In one study of 16 patients with unilateral temporal lobe epilepsy as determined by EEG, concordance of these results with the NAA/choline + creatine ratio was observed for all subjects.⁶⁵ Similar studies reported by others show that determination of the seizure focus based on MRI, MRS, and FDG-PET may be sufficient for surgical resection without invasive recordings.⁶⁶^,⁶⁷ Algorithms based on imaging and recording studies can be used for decisions on resection (Table 20-3). It remains to be demonstrated whether only one of these techniques can provide sufficient accuracy for such determination.

TABLE 20-3 Algorithm for Defining the Seizure Focus in Temporal Lobe Epilepsy

Additional information can be obtained with SPECT. Although interictal SPECT offers inferior imaging results relative to FDG-PET, SPECT may be adequate for ictal studies because of its availability and the longer half-life of the imaging agents (6 hours) compared with FDG (110 minutes).⁴⁹ Immediate postictal injection of technetium 99m hexamethyl-propyleneamine oxine followed by scanning can show cerebral hyperperfusion in the focus and surrounding areas of the epileptogenic zone.

MEG is likely to provide localization similar to EEG. As MEG becomes more available, the combination of MEG and FDG-PET or MRI and MRS may suffice for complete determination of the locus of the seizure focus without the need for ictal EEG or invasive recordings.

Extratemporal Lobe Epilepsy

Similar to localization of temporal lobe epilepsy foci, extratemporal foci are also identified on FDG-PET in interictal studies as areas of glucose hypometabolism. EEG recordings and MRI detection of abnormalities on T1-weighted images or T2 relaxometry also provide localization, but volumetric studies do not reveal extratemporal seizure areas. For example, in patients with infantile spasms and normal findings on MRI, cortical dysplastic areas are identified by hypometabolic changes seen on FDG-PET. Based on such PET characterization, successful surgical results were achieved in the early 1990s.⁴⁸^,⁵⁶ Advanced MRI techniques can now detect abnormalities in a substantial number of patients with normal conventional MRI findings.⁶⁸ Additionally, the improved resolution of MRS in combination with FDG-PET can be used in the surgical treatment of extratemporal lobe epilepsy. The use of PET fusion techniques and functional MRI data will assist in localization of the focus and facilitate the stereotactic surgical approach by providing functional mapping of the surrounding brain regions.⁶⁹^–⁷³

Brain Tumors

Applications of PET studies of brain tumors range from diagnosis and grading of gliomas to postsurgical assessment of gliomas and metastatic tumors. The consequences of therapy, including hemodynamic changes and alterations in tumor metabolism in relation to normal brain, have been used to interpret clinical observations during the evolution of these diseases. Changes in blood-brain barrier permeability and protein synthesis rates within the tumor region have provided insight into the limitations and effects of treatment on the tumor. At present, PET is used in clinical practice to determine the efficacy of treatment and to differentiate tumor recurrence from tissue necrosis.

Tumor Metabolism

Regional cerebral blood flow (CBF), cerebral blood volume (CBV), oxygen extraction fraction (OEF), and cerebral oxygen utilization (CMRO₂) have been evaluated by [¹⁵O]CO₂, [¹¹C]CO, and [¹⁵O]CO as tracers and constant infusion of [¹⁵O]H₂O.⁷⁴ Surprisingly, it has been shown that oxygen extraction and utilization are decreased in primary brain tumors in comparison to normal brain tissue.⁷⁵ Moreover, there appears to be an uncoupling of regional CBF and regional CBV. CBF in gliomas is rather variable, particularly in high-grade gliomas. For example, edematous areas surrounding the tumor have decreased blood flow and oxygen utilization but normal oxygen extraction and are therefore not considered ischemic. These metabolic characteristics are altered by dexamethasone administration or radiotherapy.⁷⁶ Dexamethasone causes a decrease in CBF and CBV in both hemispheres of patients with brain tumors, and radiotherapy effects a decrease in CMRO₂ and CBF in the tumor, with an increase in these parameters in the opposite hemisphere.⁶⁸ These findings are in accord with the rapid clinical improvement of patients with brain tumors undergoing steroid therapy. Similarly, the effects of radiotherapy on CBF and metabolism explain the clinical improvement of patients undergoing this therapy.

Tumor characterization with FDG-PET has been correlated with the histologic grade of primary brain tumors.⁷⁷^–⁸⁰ Hypermetabolism is observed in high-grade gliomas because the rate of cell growth is directly related to tumor metabolism (Fig. 20-8).⁷⁹^,⁸¹ Areas of hypermetabolism in low-grade gliomas may suggest histologic deterioration to a higher grade. Therefore, FDG-PET has prognostic value because the histologic grade of a primary brain tumor determines the prognosis and treatment options, as has been confirmed by several investigators.⁸²^,⁸³ For example, patients with MRI-detected low-grade gliomas can postpone undergoing biopsy if they are monitored carefully with serial FDG-PET and MRI. Then, when surgery is indicated, the FDG-PET profiles of tumor delimitation can be used to guide stereotactic biopsy to the areas most likely to yield the correct tumor grade.⁸⁴

FIGURE 20-8 [¹⁸F]Fluoro-2-deoxy-D-glucose–positron emission tomography (PET) (A) and gadolinium-enhanced T1-weighted magnetic resonance imaging (B) show a metastatic melanoma in the corpus callosum at the time of stereotactic radiosurgical treatment. The arrow points to the tumor in the PET image. Notice the ring of hypermetabolism surrounding a center of hypometabolism representing the lesion.

Hypometabolism, as measured by FDG-PET, has been the defining characteristic of low-grade gliomas. Areas of high glucose uptake in a low-grade glioma suggest malignant degeneration. However, differentiation of low-grade glioma histology based on FDG-PET imaging is problematic. Glucose metabolic rates are generally lower in low-grade astrocytomas and oligodendrogliomas than in normal brain tissue. Moreover, oligodendrogliomas have slightly higher metabolism than do low-grade astrocytomas. It has been suggested that histologic differentiation of these two tumors may be accomplished with [¹¹C]methionine-PET.⁸⁵ Oligodendrogliomas have significantly higher uptake of this tracer than do low-grade astrocytomas, and this observation may be related to cell density and turnover in each of these tumors. Higher cell turnover, presumably present in oligodendrogliomas,⁸⁶ may also account for this difference. During the follow-up period, FDG-PET studies have value in differentiating radiation necrosis from tumor recurrence; radiation necrosis has very low cell turnover, and consequently, that region does not accumulate FDG significantly (Figs. 20-9 to 20-11; see also Fig. 20-8). This differential diagnosis is important for patients with malignant gliomas and metastatic tumors undergoing multimodality therapy.⁸⁵^,⁸⁷

FIGURE 20-9 A, [¹⁸F]Fluoro-2-deoxy-D-glucose (FDG)–positron emission tomography (PET) (left) and magnetic resonance imaging (MRI) (right) 3 months after stereotactic radiosurgery for a melanoma. Arrows show the location of the previous tumor (presented in Fig. 20-8). B, FDG-PET and gadolinium-enhanced T1-weighted MRI at the time of recurrence, 3 months later. PET is instrumental in differentiating tumor recurrence from radiation necrosis, a distinction that cannot be ascertained with MRI. Arrows point to the tumor recurrence.

FIGURE 20-10 Axial and sagittal [¹⁸F]fluoro-2-deoxy-D-glucose–positron emission tomography scans show the site of recurrence of glioblastoma multiforme after surgical resection. Oblique arrows show the sites of recurrence, and horizontal arrows show the resection cavity. Darker areas represent higher metabolic rates. Notice the generalized glucose hypometabolism in the right cerebral hemisphere. Areas of hypometabolism in the parietal cortex and cerebellum distant from the site of the lesion represent a phenomenon called diaschisis. This reflects the lack of synaptic input from the lesioned area to the sites of hypometabolism (arrowheads).

FIGURE 20-11 The upper images show sagittal and axial gadolinium-enhanced T1-weighted magnetic resonance imaging (MRI) scans of breakdown of the blood-brain barrier (white arrowheads) related to tumor (black arrows) presence (same study as in Fig. 20-10). [¹⁸F]Fluoro-2-deoxy-D-glucose (FDG)–positron emission tomography (PET) images (middle and bottom rows) show postoperative changes and the resection cavity devoid of FDG uptake (bottom row—oblique arrows). The darker areas represent higher metabolic rates (middle row—horizontal arrows). Note that the areas shown by arrowheads on MRI represent surgical changes and are not seen as hypermetabolism on the PET image.

Several other tracers have been used in brain tumor research, but most are related to breakdown of the blood-brain barrier and add little to the already exquisite imaging capabilities of MRI with gadolinium enhancement. They do add, however, to the study of alterations in various transport mechanisms across the blood-brain barrier.⁸⁸ For example, [¹¹C]methyl-glucose measures the facilitated diffusion rate of glucose, rubidium 82 uses the same active transport carrier as potassium,⁸⁹ and [¹¹C]albumin studies can be used to assess pinocytosis mechanisms related to the transport of much larger molecules and proteins.⁸⁹^,⁹⁰ This unique ability of PET to image specific aspects of blood-brain barrier permeability makes it attractive for follow-up studies of chemotherapy trials.

The rationale for the use of amino acid tracers for imaging tumors is based on the relatively higher amino acid uptake and protein synthesis rates in tumors than in normal tissue. The excellent tumor delineation, particularly at early imaging times (10 to 15 minutes after injection), obtained with both amino acid and amino acid analogue tracers that are not substrates for protein synthesis suggests that it is the increase in transport activity that underlies the relatively higher tracer uptake in tumors.

Studies using FDOPA as an amino acid analogue (Fig. 20-12) have now shown that this tracer is sensitive for the detection of primary brain tumors and is superior to FDG (Fig. 20-13). FDOPA imaging is also helpful in the detection of tumor recurrence in the presence of radiation necrosis, but it has no specificity for tumor grade. Recent studies of amino acid PET tracers suggest that they are also more sensitive than FDG for imaging some recurrent tumors, in particular, recurrent low-grade astrocytomas. For example, the finding of high uptake versus no uptake of the amino acid [¹⁸F]fluoroethyltyrosine ([¹⁸F]FET) was shown to strongly correlate with malignant progression of nonspecific findings on MRI.⁹¹

FIGURE 20-12 Compartmental kinetic models of [¹⁸F]fluoro-L-dopa (FDOPA) uptake. Upper row, Three compartments are defined for imaging dopamine synthesis capacity in the striatum. Middle row, Two compartments account for the bidirectional movement of FDOPA in the cerebellum and other brain regions devoid of dopamine innervation. Bottom row, Two compartments also account for bidirectional movement of the major metabolite of FDOPA, 3-O-methyl-[¹⁸F]fluoro-L-dopa (3-OMFD), that is generated in the periphery and also enters the brain and contributes to the total nonspecific activity associated with F-dopa imaging. The two-compartment model (middle row) is used to model FDOPA kinetics in tumors. FDA, [¹⁸F]fluorodopamine.

FIGURE 20-13 Radiolabeled amino acids for positron emission tomographic (PET) imaging of brain tumors. The PET tracer [¹⁸F]fluoro-L-dopa (FDOPA), which has been extensively used to assess striatal dopamine system integrity, is representative of the ¹⁸F-labeled aromatic amino acid analogues recently applied to tumor imaging. FDOPA imaging at early time periods of 10 to 15 minutes after injection shows higher [¹⁸F] uptake in tumor tissue than in normal brain tissue. A and B, Comparison of magnetic resonance imaging (left), [¹⁸F]fluorodeoxyglucose-PET (middle), and FDOPA–PET (right) images of newly diagnosed tumors. Glioblastoma (A) and grade II oligodendroglioma (B) show better contrast with FDOPA for differentiating tumor and normal tissue.

(From Chen W, Silverman DH, Delaloye S, et al. ¹⁸F-FDOPA PET imaging of brain tumors: comparison study with ¹⁸F-FDG PET and evaluation of diagnostic accuracy. J Nucl Med. 2006;47:904-911.)

Other new applications of PET tracers that image important aspects of tumor biology include the use of 3′-deoxy-3′-[¹⁸F]fluorothymidine, which can serve as an index of cell proliferation.⁹²

Unfortunately, differentiation of tumor recurrence and radiation necrosis is still not definitive with these amino acid PET tracers. Therefore, PET continues as a complementary imaging technique in the management of brain tumors.⁹³ Nonetheless, PET provides clinically relevant information for precisely targeting therapy (radiosurgery, gene therapy) by identifying the most biologically active areas within the tumor mass, as defined by breakdown of the blood-brain barrier seen on other imaging modalities such as MRI and CT.

Brain Injury

PET is unique in its ability to study brain energy metabolism because it is the only imaging modality that can provide all the parameters of energy metabolism (CBF, CBV, CMRO₂, OEF, and CMRGlu) in the human brain in vivo.⁹⁴ These parameters were briefly mentioned in the section on assessment of brain tumor metabolism. Their clinical relevance is exemplified by their use in assessing aspects of neurovascular disease. Alterations in these cerebrovascular factors are intimately related to areas of cerebral ischemia and provide both therapeutic and prognostic value when analyzed in situations of stressed cerebral tissue. For example, arterial obstruction or traumatic brain injury with a decrease in cerebral perfusion pressure (CPP) can be differentiated by different PET tracers. Patterns of cerebral vascular activity can be detected by PET with ¹⁵O-, ¹¹C-, or ¹⁸F-labeled tracers, depending on the viability of the stressed tissue.⁹⁵

Brain Energy Metabolism Parameters

CBF is maintained within physiologic levels by blood pressure and by chemical autoregulation.⁹⁶ When CBF falls to critical levels, CMRO₂, OEF, and CMRGlu reflect the functional status of the tissue. Oxygen supply is continuously required in viable tissue, so OEF increases accordingly to maintain a normal CMRO₂. The uncoupling of glucose metabolic rates from CBF and oxygen extraction reflects tissue stress that may be due to ischemia, traumatic injury, or seizure disorder. These changes have been characterized in relation to CPP.⁹⁴ Briefly, a fall in CPP of up to 40% of baseline can be compensated if autoregulation is intact. A fall in CPP of 40% to 60% leads to levels of oligemia that are compensated by an increase in OEF to maintain CMRO₂ and CMRGlu within normal limits. A 60% to 80% fall in CPP reaches levels of the ischemic penumbra. In this situation, OEF cannot compensate for the fall in CBF, and CMRO₂ starts to decrease, with a consequent increase in glucose anaerobic metabolism (i.e., glycolysis). A fall of 80% or greater in CPP is accompanied by irreversible tissue damage. At this point, CBF is below critical levels, and as CBV decreases because of cerebral edema and stasis, OEF becomes variable as a result of large areas of tissue death. CMRO₂ is then further decreased because of lack of metabolism, as indicated by concomitant decreases in CMRGlu.

Clinical Implications

The diagnosis of “misery-perfusion syndrome” has implications in the clinical management of patients with stroke, head trauma, or subarachnoid hemorrhage secondary to bleeding from an aneurysm or arteriovenous malformation. Misery-perfusion syndrome is characterized by a decrease in CBF with normal CMRO₂ maintained by a compensatory increase in OEF (Table 20-4). Measures to increase CBF in this circumstance can result in progression from the phase of tapping into the perfusion reserve (also called oligemia) to true tissue stress, the ischemic penumbra, and irreversible tissue damage.⁹⁷ Such measures may include the simple use of rheologic agents and triple-H therapy (hypertension, hypervolemia, and hemodilution) or surgical procedures such as arterioplasty, extracranial-to-intracranial arterial bypass, or carotid endarterectomy. Advantage is taken of the perfusion reserve to achieve an increase in CBV. There is a consistent increase in CBF, which leads to an increase in intracranial pressure during the initial phase of exhaustion of “autoregulation,” as well as in oligemia and the ischemic penumbra (see Table 20-4). This has particularly ominous repercussions not just for patients with severe head injury but for patients with borderline high intracranial pressure from cerebral infarction or subarachnoid hemorrhage as well. Maintenance of adequate CPP becomes the sine qua non, not only in these pathologic circumstances but also during general anesthesia, when patients with brain tumors have a risk for increased intracranial pressure.

TABLE 20-4 Fall in Cerebral Perfusion Pressure and Its Effects on Brain Energy Metabolism

Prolonged periods of inadequate CPP from any pathologic situation result in the accumulation of metabolites that have an important impact in the reperfusion phase.⁹⁸ Terms such as luxury perfusion,⁹⁹ hyperperfusion, relative luxury perfusion, and true hyperemia denote levels of vasodilation and paralysis secondary to metabolic influences in the cerebral vasculature. The degree of tissue damage depends on several factors, including the type and maturity of the tissue⁹⁸ and tissue activity at the time of the metabolic demand. Determining the extent of the oligemic state and the degree to which penumbral areas have evolved to a state of irreversible damage is important for certain clinical trials and for the definition of inclusion criteria.¹⁰⁰ Only PET studies can offer the detailed regional analysis necessary for these important decisions.

Regional aberrations in cerebral metabolism also appear in unique situations such as seizures, intracranial hematomas, and head trauma.¹⁰¹ In these situations, significant uncoupling of CBF and glucose metabolism can be detected by FDG-PET studies during the acute and subacute periods (Fig. 20-14). Hypermetabolism in the acute stage of traumatic brain injury has been well characterized.¹⁰² However, its regional nature and relationship to posttraumatic events, such as areas of contusion, subclinical seizures, and relief of pressure by surgical intervention, have only recently been demonstrated by serial FDG-PET studies.¹⁰³ The pathophysiologic substrate of this hyperglycolysis has not been defined. Its presence and degree have been unequivocally related to prognosis after traumatic brain injury,¹⁰² although the repercussions for tissue recovery are currently unknown. In addition to these acute changes in cerebral metabolism that have been confirmed by PET studies, other alterations during the rehabilitative period are suggestive of brain plasticity. For instance, it has been demonstrated that recruitment of motor areas in nondamaged parts of the brain can affect recovery of lost regional function.¹⁰⁴

FIGURE 20-14 Computed tomography (CT) (left) shows a subdural hematoma after severe head trauma. [¹⁸F]Fluoro-2-deoxy-D-glucose–positron emission tomography (FDG-PET) (right) shows significant regional hypermetabolism after drainage of the hematoma. The darker areas represent higher metabolic rates. The PET study was conducted 5 days after surgery.

(From Bergsneider M, Hovda D, Shalmos E, et al. Cerebral hyperglycolysis following severe traumatic brain injury in humans: a positron emission tomography study. J Neurosurg. 1997;86:241-251.)

In Vivo Drug Monitoring

Molecular imaging with PET can also be applied to various types of pharmacokinetic and pharmacodynamic studies. For example, many drugs can be labeled with ¹¹C without altering their structure. In PET studies, the distribution of these ¹¹C-labeled drugs throughout the brain can then be determined at tracer doses. With this methodology, the distribution and temporal profile of a drug can be imaged in humans, thereby obviating the need for animal studies, whose results are often difficult to extrapolate to the human condition because of species-dependent differences in drug metabolism.

An excellent example of a PET-based pharmacokinetic study in humans was conducted with deprenyl, an irreversible monoamine oxidase B (MAO-B) inhibitor used for Parkinson’s disease.¹⁰⁵ To determine the regional MAO-B distribution in brain, [¹¹C]deprenyl was synthesized for use as a PET tracer. [¹¹C]Deprenyl-PET imaging studies then showed that the MAO-B content is 60% higher in the thalamus and basal ganglia than in cortical regions and the cerebellum. Subsequently, a series of [¹¹C]deprenyl-PET studies were used to estimate the half-time for MAO-B synthesis in vivo in individual subjects. First, a [¹¹C]deprenyl-PET scan was obtained for determining baseline values of brain MAO-B content. Before the next [¹¹C]deprenyl-PET scan, the individuals were administered deprenyl in pharmacologic doses (5 mg/day for 7 days) to achieve essentially total irreversible inhibition of MAO-B. Thereafter, a second [¹¹C]deprenyl-PET scan was obtained. Relative to the pretreatment scan values, [¹¹C]deprenyl binding after administration of deprenyl was reduced by 90%, thus indicating nearly complete inactivation of the enzyme. Multiple scans in the individuals during the next 2 months revealed a protracted recovery of MAO-B binding, which was attributed to the time course needed for synthesis of new enzyme. These data were used to calculate a 40-day half-time for MAO-B synthesis. These results provided the first in vivo measurement of the synthesis rate of a specific protein in human brain. Furthermore, these results indicated that the recommended daily clinical dose of deprenyl (5 mg twice a day) exceeded the dose necessary for therapeutic efficacy. This study elegantly illustrates how PET can be used to determine appropriate drug dosages for optimal efficacy.

PET has also been used to determine the relationship between drug dose and receptor occupancy by using a PET tracer that binds to the same receptor site as the drug to be studied.¹⁰⁶^,¹⁰⁷ In this paradigm, two PET studies are conducted. In the first study, only the tracer is administered and its receptor binding profile is determined. Then, in the second study, a pharmacologic dose of the drug is administered before injection of the tracer. Tracer binding will be reduced relative to the first study because now a fraction of the receptors are occupied by the drug. The percent reduction in tracer binding then corresponds to the percent receptor occupancy by the drug. These in vivo pharmacokinetic studies provide more accurate estimates of drug-receptor occupancy than those derived from calculations based on administered dose or drug plasma concentrations.