Shuji Tanada

Progressive loss of cortical acetylcholinesterase activity in association with cognitive decline in Alzheimer's disease: a positron emission tomography study.

We measured brain acetylcholinesterase activity in 30 patients with Alzheimers disease (AD) and 14 age‐matched controls by positron emission tomography (PET) and using a carbon 11–labeled acetylcholine analogue. Seven AD patients had repeat PET scans. The k3 values were calculated as an index of acetylcholinesterase activity in a three‐compartment analysis using the metabolite corrected arterial input function. Twenty‐eight of the 30 AD patients (14 each in the early and late onset subgroups) were retained in the study so as to equalize the range and average severity of cognitive impairment within the early and late onset subgroups. The k3 values were significantly reduced in the neocortex, hippocampus, and amygdala in the early onset AD patients, although the k3 values were significantly reduced only in the temporoparietal cortex and amygdala in the late onset AD patients. In the longitudinal study, all 7 repeat AD patients showed further reduction of cortical k3 values in the second PET scans, with a mean interval of 2 years, suggesting a progressive loss of the ascending cholinergic system from the nucleus basalis of Meynert in AD. In 37 AD patients, there was a highly significant correlation between the cortical k3 values and Mini‐Mental State Examination scores, supporting the cholinergic hypothesis in AD. Ann Neurol 2000;48:194–200

Physical performance evaluation of a 256-slice CT-scanner for four-dimensional imaging.

We have developed a prototype 256-slice CT-scanner for four-dimensional (4D) imaging that employs continuous rotations of a cone-beam. Since a cone-beam scan along a circular orbit does not collect a complete set of data to make an exact reconstruction of a volume [three-dimensional (3D) image], it might cause disadvantages or artifacts. To examine effects of the cone-beam data collection on image quality, we have evaluated physical performance of the prototype 256-slice CT-scanner with 0.5 mm slices and compared it to that of a 16-slice CT-scanner with 0.75 mm slices. As a result, we found that image noise, uniformity, and high contrast detectability were independent of z coordinate. A Feldkamp artifact was observed in distortion measurements. Full width at half maximum (FWHM) of slice sensitivity profiles (SSP) increased with z coordinate though it seemed to be caused by other reasons than incompleteness of data. With regard to low contrast detectability, smaller objects were detected more clearly at the midplane (z = 0 mm) than at z = 40 mm, though circular-band like artifacts affected detection. The comparison between the 16-slice and the 256-slice scanners showed better performance for the 16-slice scanner regarding the SSP, low contrast detectability, and distortion. The inferiorities of the 256-slice scanner in other than distortion measurement (Feldkamp artifact) seemed to be partly caused by the prototype nature of the scanner and should be improved in the future scanner. The image noise, uniformity, and high contrast detectability were almost identical for both CTs. The 256-slice scanner was superior to the 16-slice scanner regarding the PSF, though it was caused by the smaller transverse beam width of the 256-slice scanner. In order to compare both scanners comprehensively in terms of exposure dose, noise, slice thickness, and transverse spatial resolution, K=Dsigma2ha3 was calculated, where D was exposure dose (CT dose index), sigma was magnitude of noise, h was slice thickness (FWHM of SSP), and a was transverse spatial resolution (FWHM of PSF). The results showed that the K value was 25% larger for the 16-slice scanner, and that the 256-slice scanner was 1.25 times more effective than the 16-slice scanner at the midplane. The superiority in K value for the 256-slice scanner might be partly caused by decrease of wasted exposure with a wide-angle cone-beam scan. In spite of the several problems of the 256-slice scanner, it took a volume data approximately 1.0 mm (transverse) x 1.3 mm (longitudinal) resolution for a wide field of view (approximately 100 mm long) along the zeta axis in a 1 s scan if resolution was defined by the FWHM of the PSF or the SSP, which should be very useful to take dynamic 3D (4D) images of moving organs.

Age-related reduction of extrastriatal dopamine D2 receptor measured by PET.

Although the aging effect of dopamine D2 receptor in the striatum is well-documented, the effect of age on the extrastriatal dopamine D2 receptor has not been fully examined. Since the density of extrastriatal dopamine D2 receptor is very low, suitable ligands are limited. In this study, we used [11C]FLB 457 to quantify the extrastriatal dopamine D2 receptor in the living human brain. Twenty-seven healthy male subjects aged from 21 to 82 years participated in the positron emission tomography study. Extrastriatal [11C]FLB 457 binding was quantified with a reference tissue model using cerebellum as a reference region. Binding potentials corresponding to Bmax/Kd were used to evaluate age-related change. We found age-related decreases of D2 receptor binding in all measured extrastriatal regions. The decrease of D2 receptor binding was 13.8% per decade in frontal cortex, 12.0% in temporal cortex, 13.4% in parietal cortex, 12.4% in occipital cortex, 12.2% in hippocampus, and 4.8% in thalamus. These findings suggest that the amounts of D2 receptor declines in all brain regions as part of the normal aging process.

Thallium-201 myocardial tomography with intravenous infusion of adenosine triphosphate in diagnosis of coronary artery disease

OBJECTIVES The purpose of this study was to evaluate the feasibility, safety and diagnostic accuracy of thallium-201 myocardial tomography with intravenous adenosine triphosphate (ATP) infusion in patients with suspected coronary artery disease. BACKGROUND Both ATP and adenosine are potent coronary vasodilators with a very short half-life. Several studies have confirmed that the diagnostic accuracy of adenosine thallium-201 scintigraphy is comparable to that with exercise. However, a high incidence of side effects, including atrioventricular (AV) block, has also been reported. Because the appropriate infusion rate for ATP has not yet been determined, this agent has not been tested in combination with myocardial scintigraphy. METHODS The study group included 253 consecutive patients who underwent thallium-201 myocardial tomography with ATP infusion (0.16 mg/kg body weight per min for 5 min). The occurrence of adverse effects was carefully monitored. Of the 120 patients with coronary angiography, 76 had significant coronary artery disease. Tomographic images were assessed visually and by computer-quantified polar maps, and they were compared with the results of coronary angiography. RESULTS Although 56% of the patients had some adverse effects, they were transient and mild. In all patients, the ATP infusion protocol could be completed, and no patient required aminophylline; AV block occurred in only 2% of the patients. The sensitivity and specificity were 88% and 80%, respectively, by visual analysis and 91% and 86%, respectively, by computer quantification. CONCLUSIONS Thallium tomography with ATP is feasible and has a diagnostic value similar to that with adenosine for detecting coronary artery disease. In addition, it may have fewer side effects than adenosine myocardial tomography.

Extrastriatal dopamine D2 receptor density and affinity in the human brain measured by 3D PET.

The aim of the present study was to quantify the density and affinity of human extrastriatal dopamine D2 receptors using positron emission tomography (PET). [(11)C]FLB-457, a high-affinity dopamine D2 receptor antagonist with various specific radioactivities (SA) was used. Eight healthy male subjects, age 20-35 yr, participated twice or three times at different SAs (1-279 GBq/ µmol), and serial dynamic scans were performed in the 3D data acquisition mode. The peak of the specific binding was not well defined with high SA due to the flatness of the curves after 60 min but was observed within the PET measurement. In the experiment with low SA, the peak came earlier than that with high SA. Scatchard analysis was performed using the maximal specific binding value (transient equilibrium) and the radioactivity in the cerebellum as free ligand concentration. The highest density was observed in the thalamus (2.3+/-0.6 pmol/ml), followed by the temporal cortex (1.5+/-0.5 pmol/ml), hippocampus (1.4+/-0.5 pmol/ml), parietal cortex (0.9+/-0.4 pmol/ml), frontal cortex (0.8+/-0.2 pmol/ml) and occipital cortex (0.7+/-0.3 pmol/ml). There was no significant difference in K(d) values in these six regions. The present results demonstrate that dopamine D2 receptor densities in the extrastriatal regions were only 2-8% of that in the striatum. Although the density of extrastriatal dopamine D2 receptor was low, significant regional differences were observed in the present study, as reported in postmortem studies.

Age-related decline of serotonin transporters in living human brain of healthy males

There is growing interest in serotonin transporter (5-HTT) function in the human brain, since alteration in 5-HTT has been suggested in a variety of neurophychiatric disorders. Age-related decline in postsynaptic 5-HT receptors has been demonstrated in postmortem human studies and in vivo imaging studies, and has been assumed to be related to changes in mental function in the normal aging process. However, few studies have investigated the aging effect on 5-HTT in human brain in vivo, since the availability of suitable ligands has been limited. To investigate the aging effect on 5-HTT in living human brain, we performed positron emission tomography (PET) scans with a selective ligand for 5-HTT, [11C](+)McN5652. We examined 28 healthy male volunteers aged between 20 and 79 years. The uptake was quantified in the thalamus and midbrain by graphical analysis with the cerebellum as a reference tissue, and binding potential (BP) was used for the index of 5-HTT binding. There was a significant age-related decline in BP in the thalamus and midbrain. The decline in [11C](+)McN5652 binding was 9.6% per decade in the thalamus and 10.5% per decade in the midbrain.

Cardiac imaging using 256-detector row four-dimensional CT: preliminary clinical report

PurposeAlong with the increase of detector rows on the z-axis and a faster gantry rotation speed, the spatial and temporal resolutions of the multislice computed tomography (CT) have been improved for noninvasive coronary artery imaging. We investigated the feasibility of the second specification prototype 256-detector row four-dimensional CT for assessing coronary artery and cardiac function.Materials and methodsThe subjects were five patients with coronary artery disease. Contrast medium (40–60 ml) was intravenously administered at the rate of 3–4 ml/s. The patients whole heart was scanned for 1.5 s to cover at least one cardiac cycle during breathholding without electrocardiographic gating. Parameters used were 0.5 mm slice thickness, 0.5 s/rotation, 120 Kv, and 350 mA, with a half-scan reconstruction algorithm (temporal resolution 250 ms). Twenty-six transaxial datasets were reconstructed at intervals of 50 ms.ResultsThe assessability of the coronary arteries in AHA segments 1, 2, 3, 5, 6, 7, 9, and 11 was visually evaluated, resulting in 29 of 32 (90.9%) segments being assessable. Functional assessment was also performed using animated movies without banding artifacts in all cases.ConclusionsThe 256-detector row four-dimensional CT can assess the coronary artery and cardiac function using data during 1.5 s without banding artifacts.

Brain N-acetylaspartate is elevated in Pelizaeus-Merzbacher disease with PLP1 duplication.

Objective: To assess alterations in brain metabolites of patients with Pelizaeus–Merzbacher disease (PMD) with the proteolipid protein gene 1 (PLP1) duplications using quantitative proton MRS. Methods: Five unrelated male Japanese patients with PMD with PLP1 duplications were analyzed using automated proton brain examination with the point resolved spectroscopy technique (repetition and echo time of 5,000 and 30 msec). Localized spectra in the posterior portion of the centrum semiovale were acquired, and absolute metabolite concentrations were calculated using the LCModel. Results: Absolute concentrations of N-acetylaspartate (NAA), creatine (Cr), and myoinositol (MI) were increased by 16% (p < 0.01), 43% (p < 0.001), and 31% (p < 0.01) in patients with PMD as compared with age-matched controls. There was no statistical difference in choline concentration. Conclusion: The increased concentration of NAA, which could not be detected by previous relative quantitation methods, suggests two possibilities: axonal involvement secondary to dysmyelination, or increased cell population of oligodendrocyte progenitors. Elevated Cr and MI concentrations may reflect the reactive astrocytic gliosis. Our study thus emphasizes the importance of absolute quantitation of metabolites to investigate the disease mechanism of the dysmyelinating disorders of the CNS.

Distinctly abnormal brain metabolism in late-onset ornithine transcarbamylase deficiency

Objective To assess alterations in brain metabolites in patients with late-onset ornithine transcarbamylase deficiency (OTCD). Methods Six unrelated, asymptomatic Japanese late-onset OTCD patients were analyzed by proton MRS (1HMRS) using a point-resolved spectroscopy technique (repetition and echo times, 5000 and 30 ms). Localized spectra for the centrum semiovale were acquired and absolute metabolite concentrations were calculated using an LCModel. Results Compared with age-matched controls, N-acetylaspartate and creatine concentrations were normal in all patients. The glutamine (Gln) plus glutamate concentration was increased in four patients, which progressed in proportion to the clinical stage. myo-inositol (mI) could not be detected in five symptomatic patients. A decreased choline (Cho) concentration was detected in two clinically severe patients. 1HMRS after liver transplantation in one patient revealed the normalization of all metabolites. Conclusion These findings suggest progression of neurochemical events in OTCD, i.e., mI depletion and Gln accumulation followed by Cho depletion, which is reverse of that in hepatic encephalopathy, i.e., Cho depletion followed by mI depletion and Gln accumulation.

Detection of Experimental Autoimmune Myocarditis in Rats by 111In Monoclonal Antibody Specific for Tenascin-C

Background—Although the identification of inflammatory infiltrates in endomyocardial biopsy specimens is necessary for the definite diagnosis of myocarditis, the biopsy test is invasive and is not sensitive. Therefore, a new diagnostic technique for the early and noninvasive evaluation of myocarditis has been awaited. Expression of tenascin-C (TNC), one of the oligometric extracellular glycoproteins, is induced in various pathological states, including inflammation, suggesting that TNC can be a molecular marker of myocarditis. Methods and Results—An 111In anti-TNC monoclonal antibody Fab′ fragment was injected intravenously into rats with experimental autoimmune myocarditis (EAM), and the biodistribution of this radiotracer was measured. Rapid clearance of radioactivity from the blood was observed in both EAM and control rats (<1% at 6 hours after injection). Myocardial uptake of the tracer was much higher in EAM rats than in control rats (7.54-, 4.39-, and 3.51-fold at 6, 24, and 48 hours after injection, respectively). By autoradiography, high radioactivities were clearly observed in the regions indicative of inflammation in EAM rats. Single-photon emission CT imaging demonstrated the focal myocardial uptake of 111In anti-TNC Fab′ in vivo. Conclusions—Radiolabeled anti-TNC Fab′ may be useful for the noninvasive diagnosis of myocarditis.