The principle of functional and activation studies using positron emission tomography PET

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The energy demand of the brain is very high and relies almost entirely on the oxidative metabolism of glucose (see Chapter 1). Mapping of neuronal activity in the brain can be primarily achieved by quantitation of the regional cerebral metabolic rate for glucose (rCMRGlc), as introduced for autoradiographic experimental studies by Sokoloff et al. [7] and adapted for positron emission tomography (PET) in humans by Reivich et al. [8]. The cerebral metabolic rate for glucose (CMRGlc) can be quantified with PET using 2-[18F]fluoro-2-deoxyglucose (FDG) and a modification of the three-compartment model equation developed for autoradiography by Sokoloff et al. [7]. Like glucose, FDG is transported across the blood-brain barrier and into brain cells, where it is phosphorylated by hexokinase. However, FDG-6-phosphate cannot be metabolized to its respective fructose-6-phosphate analog, and does not diffuse out of the cells in significant amounts. The distribution of the radioactivity accumulated in the brain remains quite stable between 30 and 50 minutes after intravenous tracer injection, thus permitting multiple intercalated scans. Using (i) the local radioactivity concentration measured with PET during this steady-state period, (ii) the concentration-time course of tracer in arterial plasma, (iii) plasma glucose concentration, and (iv) a lumped constant correcting for the differing behavior in brain of FDG and glucose, CMRGlc can be computed pixel by pixel according to an optimized operational equation [9]. The resulting pseudocolor-coded images reflect all effects on cerebral glucose metabolism. Because of its robustness with regard to procedure and model assumptions, the FDG method has been employed in many PET studies.

Almost all commonly applied methods for the quantitative imaging of CBF are based on the principle of diffusible tracer exchange. Using 15O-labeled water administered either directly by intravenous bolus injection or by the inhalation of 15O-labeled carbon dioxide, which is converted into water by carbonic anhydrase in the lungs, CBF can be estimated from steady-state distribution or from the radioactivity concentration-time curves in arterial plasma and brain. Typical measuring times range between 40 seconds and 2 minutes, and, because of the short biological half-life of the radiotracers, repeat studies can be performed [10, 11].

Various PET methods have been developed for determining the cerebral metabolic rate for oxygen (CMRO2), using continuous [11] or single-breath inhalation [12] of air containing trace amounts of 15O-labeled molecular oxygen. All require the concurrent estimation or paired measurement of CBF in order to convert the measured oxygen extraction fractions (OEFs) into images of CMRO2 as given by the product of arterial oxygen concentration, local OEF and local CBF. Because 15O has a short half-life (123 seconds), an on-site cyclotron is necessary; this and other methodological complexities limit the use of CMRO2 as a measure of brain function. Application of this method for detection of penumbra tissue is described in Chapter 1.

Functional activation studies as they are used now rely primarily on the hemodynamic response, assuming a close association between energy metabolism and blood flow. Whereas it is well documented that increases in blood flow and glucose consumption are closely coupled during neuronal activation, the increase in oxygen consumption is considerably delayed, leading to a decreased oxygen extraction fraction (OEF) during activation [13]. PET detects and, if required, can quantify changes in CBF and CMRGlc accompanying different activation states of brain tissue. The regional values of CBF or CMRGlc represent the brain activity due to a specific state, task or stimulus in comparison to the resting condition, and color-coded maps can be analyzed or correlated to morphological images. Due to the radioactivity of the necessary tracers, activation studies with PET are limited to a maximum of 12 doses of 15O labeled tracers, e.g. 12 flow scans, or two doses of 18F-labeled tracers, e.g. two metabolic scans. Especially for studies of glucose consumption, the time to metabolic equilibrium (20-40 min) must be taken into consideration, as well as the time interval between measurements

required for isotope decay (HT for 18F 108 min, for 15O 2 min).

PET used to quantify the regional concentration of these tracers relies on the labeling of the compounds with short-lived cyclotron-produced radioisotopes (e.g. 150,11C, 13N, 18F) which are characterized by a unique decay scheme. A positron, i.e. a positively charged particle of the mass of an electron, is emitted from a labeled probe molecule. Following emission from the atomic nucleus, the positron takes a path marked by multiple collisions with ambient electrons. Approximately 1-3 mm from its origin, it has lost so much energy that it combines with an electron, resulting in the annihilation of the two oppositely charged particles by the emission at an angle of 180° ± 0.5° of two 511 keV (kilo electron volt) photons that are recorded as coincident events, using pairs of uncol-limated (convergent) detectors facing each other. Therefore, the origin of the photons can be localized directly to the straight line between these coincidence detectors. State-of-the-art PET scanners are equipped with thousands of detectors arranged in up to 24 rings, simultaneously scanning 47 slices of <5 mm thickness. Pseudocolor-coded tomographic images of the radioactivity distribution are then reconstructed from the many projected coincidence counts by a computer, using CT-like algorithms and reliable scatter and attenuation corrections. Typical in-plane resolution (full width at half-maximum) is <5 mm; 3D data accumulation and reconstruction permits imaging of the brain in any selected plane

In PET, radioactive tracers can be used to detect and quantify changes in cerebral blood flow (CBF) and cerebral metabolic rate of glucose (CMRGlc). Color-coded maps of different activation states of brain tissue can be analyzed or coregistered to morphological images.

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