William Robeson

The metabolic topography of parkinsonism.

We used [18F]fluorodeoxyglucose/positron emission tomography (18F-FDG/PET) and a statistical model of regional covariation to study brain topographic organization in parkinsonism. We studied 22 patients with Parkinsons disease (PD), 20 age-matched normal volunteers, and 10 age- and severity-matched patients with presumed striatonigral degeneration (SND). We used FDG/PET to calculate global, regional, and normalized metabolic rates for glucose (GMR, rCMRglc, rCMRglc/GMR). Metabolic parameters in the three groups were compared using an analysis of variance, with a correction for multiple comparisons, and discriminant analysis. The scaled subprofile model (SSM) was applied to the combined rCMRglc dataset to identify topographic covariance profiles that distinguish PD patients from SND patients and normals. GMR, rCMRglc, and rCMRglc/GMR were normal in PD; caudate and lentiform rCMRglc/GMR was reduced in the SND group (p < 0.01). SSM analysis of the combined group of patients and normals revealed a significant topographic profile characterized by increased metabolic activity in the lentiform nucleus and thalamus associated with decreased activity in the lateral frontal, paracentral, inferior parietal, and parietooccipital areas. Individual subject scores for this profile were significantly elevated in PD patients compared with normals and SND patients (p < 0.001) and discriminated the three groups. In the PD group, subject scores for this factor correlated with individual subject Hoehn and Yahr (H&Y) scores (p < 0.02), and with quantitative rigidity (p < 0.01) and bradykinesia (p < 0.03) ratings, but not with tremor ratings. SSM analysis of right-left metabolic asymmetries yielded a topographic contrast profile that accurately discriminated mildly affected PD patients (H&Y Stage I) from normals. Our findings demonstrate that abnormal topographic covariance profiles exist in parkinsonism. These profiles have potential clinical application as neuroimaging markers in parkinsonism.

Striatal 18F-DOPA Uptake: Absence of an Aging Effect

l-[18F]6-Fluoro-DOPA (l-[18F]6-fluoro-3,4-dihydroxyphenylalanine; FDOPA) has been used with quantitative positron emission tomography (PET) to assess presynaptic nigrostriatal dopaminergic function in life. The relationship of estimated kinetic rate constants for striatal FDOPA uptake [Ki(FDOPA)] to the normal aging process has been the subject of conflicting reports. Resolution of this issue has been hampered by methodological differences in previous FDOPA/PET investigations. We studied 19 healthy normal subjects (aged 27–77 years) and measured striatal Ki-(FDOPA) according to each of the earlier methods. While significant correlations (p < 0.005) existed between Ki(FDOPA) values estimated by the various techniques, none correlated with normal aging. We conclude that normal striatal Ki(FDOPA) values estimated using quantitative FDOPA/PET are uncorrelated with the aging process.

Combined FDOPA and 3OMFD PET Studies in Parkinson's Disease

This chapter presents the studies of 6-[ 18 F]fluoro-L-dopa (FDOPA)/positron emission tomography (PET) to determine the quantitative parameters that correlate closely with independent disease severity measures and discriminate reliably between patients with mild early disease, or with preclinical involvement, and normal control subjects. Five classical Parkinsons disease (PD) patients with mild or moderate clinical involvement and without dementia were studied with quantitative FDOPA and 3-O-MFD/PET. The control group consists of three normal volunteer subjects. All subjects fasted overnight prior to the PET scanning. All anti-Parkinsonian medications were discontinued at least 12 h before PET investigations. PET studies were performed using the SuperPETT 3000 tomograph. All subjects received 200 mg carbidopa 1.5 h before the study and 185–370 MBq of FDOPA was injected intravenously. The use of 3-O-MFD parameters in the FDOPA compartmental model allows one to simplify the model without making assumptions that are otherwise required. The results show that striatal dopadecarboxylation (DDC) activity estimated from a compartmental modeling approach is similar to the graphically derived unidirectional influx constant in discriminating normals from PD patients. In addition, unidirectional transport rate constant and various estimates of striatal DDC activity have similar correlations with disease severity. This suggests that with present PET methods, clinically relevant information can be obtained from a simple graphical approach rather than a more computationally demanding compartmental technique.UNLABELLED PET has been used to quantify striatal 6-[18F]fluoro-L-dopa (FDOPA) uptake as a measure of presynaptic dopaminergic function. It has been suggested that the estimation of dopa-decarboxylation (DDC) rate, kD3, using a compartmental approach to dynamic FDOPA/PET data, can provide a better objective marker of parkinsonism. This modeling process, however, requires many assumptions to estimate DDC activity with acceptable errors. METHODS We combined FDOPA 3-O-methyl-fluorodopa PET studies on three normal subjects and five Parkinsons disease patients. RESULTS The contradicted modeling assumptions are: (a) the rate constants across the blood-brain barrier, KD1 and kD2, for 3OMFD and FDOPA were in similar range (ratio approximately equal to 1) and thus not equal to assumed values of KM1/KD1 of 2.3 derived from rat studies and applied to human FDOPA studies and (b) the KD1/kD2 ratio for frontal cortex was not equal to that for the striatum (0.70 +/- 0.15 versus 1.07 +/- 0.3; p < 0.002). Discriminant analyses indicate that simple estimates like the striatum-to-occipital ratio, or the graphically derived unidirectional transport rate constant (KiFD) separate normals from Parkinsons disease patients at least as accurately as estimates of striatal DDC activity (kD3). CONCLUSION Measurements of striatal DDC activity with dynamic FDOPA/PET and compartmental modeling may be based on incorrect assumptions. Even though such complex models yield microparameters that may be applicable to certain clinical research demands, they may produce misleading results in other experimental settings.

Quantitative Brain PET. Comparison of 2D and 3D Acquisitions on the GE Advance Scanner.

PURPOSE: Recent developments in the design of positron emission tomography (PET) scanners have made three-dimensional (3D) data acquisition attractive because of significantly higher sensitivity compared to the conventional 2D mode (with lead/tungsten septa extended). However, the increased count rate in 3D mode comes at the cost of increased scatter, randoms, and dead time. Several schemes to correct for these effects have been proposed and validated in phantom studies. In this study, we evaluated the overall improvement afforded by 3D imaging in quantitative human brain PET studies carried out at our institution.METHODS: Subjects were studied using sequential/interleaved 2D and 3D data acquisition with a GE Advance scanner. We calculated regional and global cerebral glucose metabolism with [(18)F]flourodeoxyglucose (FDG) and estimated rate constants for striatal [(18)F]fluorodopa (FDOPA) uptake.RESULTS: FDG: Global mean glucose metabolic rates were in almost complete agreement (within 1%) between the two modes whereas the regional differences ranged from -7.7% to +9% for all cortical structures. However, for small regions (<2 cm(2)) like caudate nuclei, the maximum difference was 14.7%. FDOPA: A significant improvement in image quality was evident in 3D mode and there was complete agreement between the estimated parameters in the two scanning modes for the same noise equivalent counts: Striatal-to-occipital ratio (SOR) and striatal FDOPA uptake (K(i)(FD)) had mean differences of less than 2% and 5%, respectively.CONCLUSIONS: 3D FDG studies can be done with either half the injected dose or half the scan duration to a comparable 2D study. 3D PET imaging has distinct advantages over 2D in the quantitative fluorodopa studies.

Fluorodopa Positron Emission Tomography with an Inhibitor of Catechol-O-Methyltransferase: Effect of the Plasma 3-O-Methyldopa Fraction on Data Analysis

Fluorodopa (FDOPA) is an analogue of L-dihydroxyphenylalanine (L-dopa) used to assess the nigrostriatal dopamine system in vivo with positron emission tomography (PET). However, FDOPA/PET quantitation is complicated by the presence of the 3-O-methyl-FDOPA (30MFD) fraction in brain and plasma. Pretreatment with entacapone (OR-611), a peripheral catechol O-methyltransferase (COMT) inhibitor, greatly reduces the plasma 30MFD fraction and provides an ideal situation to evaluate the contribution of the plasma 30MFD fraction in several kinetic models of FDOPA uptake. We performed FDOPA/PET with and without the OR-611 preadministration in six Parkinsons disease (PD) patients. We measured the time-course of the plasma FDOPA and 30MFD fractions using high-pressure liquid chromatography (HPLC). We calculated striato-occipital ratios (SOR), and estimated the striatal FDOPA uptake rate constant graphically using the plasma FDOPA and occipital tissue time activity curves (KiFD and KiOCC, respectively). We also estimated striatal dopa decarboxylase (DDC) activity (k3D) using a model incorporating independent measurements of 30MFD transport kinetic rate constants. With the preadministration of OR-611, the pharmacological efficiency in plasma was prolonged significantly (21.1–37.7%; p < 0.01). We also observed significant mean elevations in SOR and KiOCC by 21.8 and 53.5%, respectively (p < 0.05). KiFD and k3D did not show significant change. We conclude that OR-611 prolongs the circulation time of FDOPA in the plasma but does not alter rate constants for striatal FDOPA uptake or decarboxylation.

Synthesis of 6-[18F]fluorodopamine with a synthetic unit made up of primarily sterile disposable components and operated by a master slave manipulator

Abstract A synthetic procedure for the routine preparation of 6-[18F]fluorodopamine has been developed. The synthesis is based on electrophilic fluorination of a 6-mercurated dopamine precursor. Fluorodemercuration of the dopamine precursor using [18F]acetylhypofluorite and hydrolysis by a mixture of acetic anhydride and HI gave the desired radiopharmaceutical with a radiochemical yield of 13.7 ± 0.7% calculated at the end of synthesis based on five synthetic preparations (without decay correction) and also based on the amount of total [18F]F2 recovered from the target. Radiochemical purity as well as chemical purity were > 98%. In order to maintain good sterility and pyrogenicity, the synthetic unit is made up of mostly sterile disposable components that are readily available. The routine operations of the synthetic unit are carried out in a closed hot cell, using a Master Slave Manipulator arm. Since no manual handling of radioactivity is involved, the operation of the synthetic unit is radiation safe and the radiation exposure to the operator is minimized.

Fourier Amplitude and Phase Analysis in the Clinical Evaluation of Patients with Cardiomyopathy

Fifty-four patients with a cardiomyopathy were studied by RNCA and Fourier amplitude and phase image analysis. The study group included patients with ischemic cardiomyopathy (27) and an equal number of patients with a primary cardiomyopathy: drug-induced (22), idiopathic (three), radiation-induced (one), and amyloidosis (one). Twenty-eight patients had rest studies alone and 26 had both rest and stress studies (80 total). The mean rest LVEF in the ischemic group was 27.9%, in the drug-induced group 36.5%, and in the idiopathic group 30%. The stress LVEF decreased in 92% of patients with ischemic cardiomyopathy and 45% of patients with primary (drug-induced) cardiomyopathy. Fourier amplitude and phase images were generated for each study. Amplitude and phase images were abnormal in all patients with an ischemic cardiomyopathy. LV amplitude abnormalities were regional and phase was directional. A zone of dysynergy on phase analysis was present in 44% of patients with ischemic cardiomyopathy. In the drug-induced primary cardiomyopathy group, all patients had abnormal amplitude and 86% had abnormal phase. Amplitude abnormalities were global rather than regional and phase patterns were nondirectional. Only one patient had a zone of dysynergy on the phase image. We conclude that the stress LVEF alone cannot consistently differentiate between ischemic and primary cardiomyopathies and that Fourier amplitude and phase analysis may be useful in determining the etiology of a cardiomyopathy (ischemic vs primary).

Early detection of anthracycline-induced cardiotoxicity by stress radionuclide cineangiography in conjunction with Fourier amplitude and phase analysis.

Thirty-three cases of anthracycline related cardiotoxicity occurred in our institution in patients with a previously negative cardiovascular history, physical examination, and normal ECG. A total of 95 RNCA studies were performed in this group (73 studies Included both rest and exercise RNCA). Twenty-one patients had two or more serial studies. Seventeen had a normal, baseline prechemotherapy study and 16 had studies done following the initiation of therapy. Fourier analysis, consisting of amplitude and phase images, were created for each study. In the subset with a baseline study, the rest LVEF became abnormal first in two of 17 patients (12%), the rest or stress LVEF in ten of 17 (59%), the rest Fourier image analysis in ten of 17 (59%), and the rest or stress Fourier image analysis in 16 of 17 (94%). In the subset without a baseline study, the rest LVEF was abnormal in ten of 16 (63%), the rest or stress LVEF in 15 of 16, (94%), the rest Fourier image analysis in 16 of 16 (100%), and the rest or stress Fourier image analysis in 16 of 16 (100%). The authors conclude that: 1) the exercise RNCA is superior to the rest RNCA alone in the early detection of anthracycline related cardiotoxicity, 2) the single most sensitive indicator of cardiotoxicity is Fourier image analysis; and 3) sequential rest and stress RNCA studies with Fourier amplitude and phase analysis is the most sensitive, noninvasive method of evaluating patients who receive potentially cardiotoxic agents.

A new approach to the measurement of resolution and sampling on a positron emission tomograph

Two technical difficulties underlie the accurate determination of spatial resolution in positron emission tomography (PET): (1) measuring the full-width half-maximum (FWHM) and full-width tenth-maximum (FWTM) from undersampled profiles; (2) measuring axial resolution from multiple reconstructed data sets. To address the first problem, a technique that involves a quadratic estimation of the peak of the profile distribution was developed. This method was compared with the standard technique of Gaussian fitting and was found to be as accurate for constant background distributions. For axial resolution, a second method involving a single scan and imaging of line sources oriented 45 degrees to the axis of the scanner was proposed. Axial FWHM estimations were achieved by deconvolving the values obtained with line spread functions from sources placed parallel to the axis of the scanner. This technique was validated by comparing the results with those obtained by others using a multiple-scan technique on a similar machine. >

Combined Fourier amplitude and phase imaging in patients with coronary artery disease

ourier amplitude and phase image analysis were evaluated in 66 patients. Thirty patients served as a control group and 36 had coronary artery disease (CAD). Each patient in our control group had a rest and exercise radionuclide cineangiogram (RNCA) study (60 total). The amplitude and phase images for controls were uniform. No statistically significant difference in the histogram distribution of amplitude or phase occurred between rest and exercise. Twenty-five patients with CAD had a prior myocardial infarction (Ml). Fourier analysis, when compared to the left ventricular ejection fraction (LVEF) and visual cine wall motion analysis, improved the sensitivity of the rest RNCA study to detect CAD from 68% to 92%. Regional Fourier amplitude and phase image analysis demonstrated an 85% sensitivity in localizing regions of previous infarction. Thirteen of 25 patients with prior Ml and an additional 11 patients with recent onset of angina but no previous infarction, had exercise RNCA studies. When compared to cardiac catheterization data, regional Fourier amplitude and phase image analysis demonstrated sensitivities of 87% and 80%, respectively, in correctly identifying clinically significant major coronary artery involvement in these two subsets of patients. Fourier amplitude and phase image analysis were also able to distinguish normals from patients with previous Ml, and patients with CAD but no prior infarction. All comparisons were statistically significant. We conclude that the semiquantitative image analysis of Fourier amplitude and phase data increases the clinical utility of the RNCA study in patients with CAD.