The precision of positron emission tomography: theory and measurement

The limits of quantitation with positron emission tomography (PET) are examined with respect to the noise propagation resulting from radioactive decay and other sources of random error. Theoretical methods for evaluating the statistical error have been devised but seldom applied to experimental data obtained on human subjects. This paper extends the analysis in several ways: (1) A Monte Carlo method is described for tracking the propagation of statistical error through the analysis of in vivo measurements; (2) Experimental data, obtained in phantoms, validating the Monte Carlo method and other methods are presented; (3) A difference in activation paradigm, performed on regional CBF (rCBF) data from five human subjects, was analyzed on 1.6-cm diameter regions of interest to determine the mean fractional statistical error in PET tissue concentration and in rCBF before and after stereotactic transformation; and (4) A linear statistical model and calculations of the various statistical errors were used to estimate the magnitude of the subject-specific fluctuations under various conditions. In this specific example, the root mean squared (RMS) noise in flow measurements was about three times higher than the RMS noise in the concentration measurements. In addition, the total random error was almost equally partitioned between statistical error and random fluctuations due to all other sources.     

Left ventricular diastolic dysfunction as assessed by echocardiography in metabolic syndrome.

The purpose of the present study was to elucidate the cardiac structure and function in patients who have metabolic syndrome but no history of cardiovascular disease by analyzing echocardiographic findings. Echocardiographic examination was performed to screen for cardiovascular disease in 135 patients who were in their sixties. Patients were divided into metabolic syndrome (n=65, age: 65+/-2.7 years) and non-metabolic syndrome (n=70, age: 66+/-2.5 years) groups based on the criteria for metabolic syndrome proposed by the Japanese Society of Hypertension and seven other societies in 2005. The left ventricular (LV) wall thickness and dimension were measured by M-mode echocardiography. The relative wall thickness, LV mass index, and LV ejection fraction (LVEF) were calculated. LV diastolic function was assessed by the peak velocity of early rapid filling (E velocity) and the peak velocity of atrial filling (A velocity), and the ratio of E to A (E/A) was assessed by the transmitral flow. The Tei index, which reflects both LV diastolic and systolic function, was also calculated. There were no differences in relative wall thickness, LV mass index, or LVEF between the two groups. However, both the EIA and Tei index were significantly different between the metabolic syndrome (0.66+/-0.14 and 0.36+/-0.07, respectively) and non-metabolic syndrome (0.88+/-0.25 and 0.29+/-0.09) groups (p<0.001). These results indicate that patients with metabolic syndrome can have cardiac diastolic dysfunction even if they have neither LV hypertrophy nor systolic dysfunction.     

A human friendly reporting and database system for brain PET analysis

We have developed a human friendly reporting and database system for clinical brain PET (Positron Emission Tomography) scans, which enables statistical data analysis on qualitative information obtained from image interpretation. Our system consists of a Brain PET Data (Input) Tool and Report Writing Tool. In the Brain PET Data Tool, findings and interpretations are input by selecting menu icons in a window panel instead of writing a free text. This method of input enables on-line data entry into and update of the database by means of pre-defined consistent words, which facilitates statistical data analysis. The Report Writing Tool generates a one page report of natural English sentences semi-automatically by using the above input information and the patient information obtained from our PET center’s main database. It also has a keyword selection function from the report text so that we can save a set of keywords on the database for further analysis. By means of this system, we can store the data related to patient information and visual interpretation of the PET examination while writing clinical reports in daily work. The database files in our system can be accessed by means of commercially available databases. We have used the 4th Dimension database that runs on a Macintosh computer and analyzed 95 cases of^I8F-FDG brain PET studies. The results showed high specificity of parietal hypometabolism for Alzheimer’s patients.     

Arpp,a new homolog of carp,is preferentially expressed in type 1 skeletal muscle fibers and is markedly induced by denervation

In this study, we isolated and characterized a murine counterpart of the human Arpp (hArpp) gene. Sequence analysis revealed that the murine Arpp (mArpp) gene is almost identical to the Ankrd2 gene, which has recently been isolated as a mouse gene induced in stretched skeletal muscle. The mArpp gene encodes a protein of 332 amino acids that contains four well-conserved ankyrin-repeat domains in the central portion of the protein. The amino acid sequence of mArpp protein (mArpp) is highly homologous to that of mouse cardiac-restricted ankyrin-repeat protein (Carp), which is proposed to be a putative genetic marker for cardiac hypertrophy. Immunohistochemical analysis revealed that mArpp is preferentially expressed in type 1 skeletal muscle fibers, and that mArpp is localized in both the nucleus and the sarcomeric I-band of muscle fibers, suggesting that Arpp may function as a nuclear and sarcomeric protein. Furthermore, mArpp was also expressed in neurons of the cerebellum and cerebrum, the islets of Langerhans in the pancreas, and the esophageal epithelium, suggesting that mArpp may play a functional physiologic role in brain, pancreas, and esophagus as well as in type 1 muscle fibers. Interestingly, although mArpp was localized in both nucleus and cytoplasm in neurons, its localization was restricted to nucleus in pancreas and esophagus, suggesting that intracellular localization of mArpp is regulated in a tissue-specific manner. Furthermore, we found that mArpp- and Carp-expression in skeletal muscle were markedly up-regulated after denervation. Although the elevated expression level of Carp was kept only for two weeks after denervation, that of Arpp was kept at least for 4 weeks, suggesting that mArpp and Carp may play distinct functional roles in denervated skeletal muscle.     

Quantitative evaluation of regional pulmonary ventilation using PET and nitrogen-13 gas

A new quantitative method, "Simultaneous Exponential Equation method" (SEE), has been developed for the analysis of pulmonary ventilation studies using 13N-labeled nitrogen gas and positron emission computed tomography. This method uses Kety's model assuming insolubility of nitrogen gas in blood or tissues. Activity in poorly ventilated regions does not reach the equilibrium in the so-called equilibrium scan (EQ) performed following 3 or 4 min of washin. Therefore EQ images do not represent lung volume images nor do they provide the initial value of washout phase. Our method corrects for these transient phenomena observed during EQ scan and yields idealistic equilibrium state images (lung volume images) as well as more accurate regional ventilatory time constants than a modified Stewart-Hamilton (A/H) method and tomograms of high resolution.     

Vascular reserve in chronic cerebral ischemia measured by the acetazolamide challenge test: comparison with positron emission tomography.

PURPOSETo determine the value of the acetazolamide challenge test with stable xenon-enhanced CT (Xe CT) for making therapeutic decisions in patients with chronic cerebrovascular disease.METHODSWe compared the Xe CT-measured acetazolamide response with various measures obtained by positron emission tomography. We performed both a positron emission tomographic scan and a Xe CT study in 11 patients with chronic cerebral ischemic diseases within a 1-week interval. An increase of cerebral blood flow after injection of acetazolamide was expressed as delta AT. Regional cerebral blood flow, cerebral oxygen metabolism, oxygen extraction fraction, and cerebral blood volume were measured with oxygen-15-labeled gases by positron emission tomography.RESULTSIn low-cerebral blood flow regions, decreased delta AT was accompanied by a significant elevation of oxygen extraction fraction and cerebral blood volume, compared with oxygen extraction fraction and cerebral blood volume in regions of normal delta AT. Plotting of regional data indicated that delta was significantly dependent on oxygen extraction fraction and cerebral blood volume. The area of decreased vascular reserve determined by the Xe CT image corresponded to the area of "misery perfusion" determined by positron emission tomography.CONCLUSIONThe acetazolamide challenge test with Xe CT may offer an alternative to positron-emission tomography in detecting lesions with elevated oxygen extraction fraction and cerebral blood volume (misery perfusion) that result from chronic hemodynamic stress.     

Gas-tissue autoradiography using [15O] molecular oxygen for visualization of mitochondrial oxygen fixation in brain slices

We have developed a novel in vitro autoradiographic method of visualizing oxygen fixation using [15O]O(2). Brain slices (400 microm) are preincubated in Krebs-Ringer phosphate buffer and exposed to [15O]O(2) with carrier O(2) for 10 min on slide glass or on a Millicell-CM membrane in a chamber. After the 15O(2) exposure, the brain slices are placed in contact with an imaging plate. The autoradiograms are analyzed with MacBas to obtain images of the distribution of radioactivity. The [15O]O(2) fixation was more extensive in the gray matter (striatum, thalamus and cerebral cortex) than in the white matter. The fixation of [15O]O(2) in brain slices decreased dose dependently with NaCN concentration. These results indicate that [15O]O(2) is converted into [15O]H(2)O in the brain tissue according to the activity of mitochondrial electron transfer and remains in the tissue. This method provides information regarding the basic oxygen consumption of brain slices of rat and mouse under conditions of sufficient O(2) delivery, which reflects mitochondrial electron transport.     

Application of PET-MRI registration techniques to cat brain imaging

In positron emission tomography (PET) studies of diseased animals, it is very useful to have accurate anatomical information as a reference. In human studies, anatomical information is usually obtained from magnetic resonance imaging (MRI) of the subject with retrospective registration of the subject's PET image to the MRI. A number of PET-MRI registration techniques are used for this purpose. However, the utility of these methods has not been tested for animals image registration. This paper studies the feasibility of applying two currently used human brain PET-MRI registration techniques to cat brain images. METHODS: Three cats were anesthetized with isoflurane gas, and PET images were acquired with H(2)(15)O, benzodiazepine receptor ligand 11C-flumazemil (FMZ), dopamine receptor ligand 11C-nemonapride (NEM) and fluorodeoxy glucose (18F-FDG). The four PET scans were acquired consecutively within the same day while the cat remained fixed in the scanner. We also obtained T1-weighted and T2-weighted MRI of the cats in a 4.7 T unit. The PET images were registered to MRI using two human brain registration techniques: a semi-automatic method (SAM), which is a two-step method based on the extraction of the midsagittal plane, and an automatic method (AMIR) method that minimizes PET pixel variance within spatially connected segments determined by MRI. RESULTS: T2-weighted MRI provided better structural information than T1 MRI. FMZ did, while FDG or H(2)O PET images did not, provide a structural outline of the brain. The FMZ PET image was registered to MRI satisfactorily using SAM. The striatum visualized in nemonapride PET image re-sliced with the same parameters matched the striatum identified in T2-weighted MRI. Registration by AMIR was successful by inspection for FMZ, FDG or H(2)O PET images in only one of the three cats. The registration error of SAM was estimated to be less than 2 mm or 2 degrees. CONCLUSION: A satisfactory registration of FMZ-PET to T2-weighted MRI of the cat brain was obtained by a two-step manual registration technique. This will enhance the usefulness of PET in the field of cerebral pathophysiology.     

Functional status and active life expectancy among senior citizens in a small town in Japan

The objectives of this study were to understand transition patterns and mechanisms of functional status, and to estimate active life expectancy (ALE) among senior citizens in a small town in Japan. With data drawn from surveys conducted annually from 1998 to 2002 (n=638 at baseline), prevalence and incidence of functional disability in activities of daily living (ADL) and instrumental activities of daily living (IADL) were described and compared between the sexes. Then relationships between potential predictors and functional decline through a 4-year follow-up were examined using logistic regression. Finally, active and disabled life expectancy was estimated by Katz's method. At baseline, 9 and 12% of subjects were dependent in performing ADL and IADL, respectively. Prevalence and incidence rates increased with age. The risk of mortality increased by 2.2-5.0-fold when the subject was functionally dependent at the previous year. Advanced age, difficulty in walking and poor interest were shown to be significant predictors of loss of independence in ADL. Mean durations with disability in ADL and IADL among women were longer than among men by around 1 year. Population-specific preventive care programs considering physical, cognitive and social aspects are needed not only to maximize ALE but also to improve quality of life during survival period with disability especially in old women.