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In this study, we developed a simple and robust semi-automatic method to measure the right ventricle to left ventricle (RV-to-LV) transit time (TT) in mice using 2-[/sup 18/F]fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET). The accuracy of the method was first evaluated using a 4-D digital dynamic mouse phantom. The RV-to-LV TTs of twenty-nine mouse studies were measured using the new method and compared to those obtained from the conventional ROI-drawing method. The results showed that the new method correctly separated different structures (e.g., RV, lung, and LV) in the PET images and generated corresponding time activity curve (TAC) of each structure. The RV-to-LV TTs obtained from the new method and ROI method were not statistically different (p=0.20; r=0.76). We expect that this fast and robust method is applicable to the pathophysiology of cardiovascular diseases using small animal models such as rats and mice.

4-[F-18]fluoro- N -{2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl}- N -(2-pyridinyl)benzamide, a selective serotonin 1A (5-HT 1A ) molecular imaging probe, was used in conjunction with positron emission tomography (PET) for quantification of 5-HT 1A receptor densities in the living brains of Alzheimer's disease patients (ADs) ( n = 8), subjects with mild cognitive impairment ( n = 6), and controls ( n = 5). ADs had receptor densities significantly decreased in both hippocampi (binding potential: controls 1.62 ± 0.07; ADs 1.18 ± 0.26) and also in raphe nuclei (controls 0.63 ± 0.09; ADs 0.37 ± 0.20). When volume losses are included, 5-HT 1A losses are even more severe (i.e., average mean decreases of 24% in mild cognitive impairment patients and 49% in ADs). A strong correlation of 5-HT 1A receptor decreases in hippocampus with worsening of clinical symptoms (Mini Mental State Exam scores) was also found. Moreover, these decreases in 5-HT 1A receptor measures correlate with decreased glucose utilization as measured with 2-deoxy-2-[F-18]fluoro- d -glucose PET in the brains of ADs (standardized uptake values; globally: controls 0.89 ± 0.04, ADs 0.72 ± 0.04; posterior cingulate gyrus: controls 1.05 ± 0.09, ADs 0.79 ± 0.11). They also inversely correlate with increased neuropathological loads measured with 2-(1-{6-[(2-[F-18]fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene)malononitrile PET in several neocortical regions in the same subjects. The in vivo observations were confirmed independently by in vitro digital autoradiography with 4-[F-18]fluoro- N -{2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl}- N -(2-pyridinyl)benzamide and 2-(1-{6-[(2-[F-18]fluoroethyl)(methyl)amino]-2-naphthyl}-ethylidene)malononitrile on brain tissue specimens from two ADs and three nondemented subjects.

The authors used 2-(1-{6-[(2-[ 18 F]fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene)malononitrile ([ 18 F]FDDNP), a hydrophobic radiofluorinated derivative of 2-{1-[6-(dimethylamino)-2-naphthyl]ethylidene}malononitrile (DDNP), in conjunction with positron emission tomography to determine the localization and load of neurofibrillary tangles (NFTs) and β-amyloid senile plaques (APs) in the brains of living Alzheimer disease (AD) patients. Previous work illustrated the in vitro binding characteristics of [ 18 F]FDDNP to synthetic β-amyloid(1–40) fibrils and to NFTs and APs in human AD brain specimens. In the present study, greater accumulation and slower clearance was observed in AP- and NFT-dense brain areas and correlated with lower memory performance scores. The relative residence time of the probe in brain regions affected by AD was significantly greater in patients with AD (n=9) than in control subjects (n=7; p=0.0007). This noninvasive technique for monitoring AP and NFT development is expected to facilitate diagnostic assessment of patients with AD and assist in response-monitoring during experimental treatments.

Striatal 6-[ 18 F]fluoro-L-DOPA (FDOPA) kinetic rate constants were measured by positron emission tomography (PET) in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated squirrel monkeys. After scanning, stereological counts of dopaminergic neurons were done in substantia nigra, and dopamine (DA) and metabolite concentrations were determined in the caudate, putamen, and substantia nigra. Graded doses of MPTP produced animals with mild to moderate reductions (10-35%) in dopaminergic neurons, where the percent of cell loss was proportional to the amount of MPTP given. Striatal DA and metabolite concentrations were relatively unchanged in animals given 1.0 and 1.5 mg/kg of MPTP, but were significantly reduced after 2.0 mg/kg of MPTP. All animals injected with a single dose of MPTP showed no overt signs of parkinsonism. In contrast, DA and metabolite concentrations in the substantia nigra were significantly reduced for all MPTP-treated animals. Reduction of dopaminergic indices in the substantia nigra did not parallel reductions in the striatum, indicating differential sensitivity of the nigrostriatal pathway to the neurotoxic effects of MPTP. The percent change in FDOPA uptake (Ki) and decarboyxlation (k 3 ) after MPTP showed significant positive correlations to striatal DA levels, but not to the number of dopaminergic neurons. This suggests that FDOPA is a good index of striatal DA levels.

The peripherally born metabolite of FDOPA, 3-O-Methyl-FDOPA (3OMFD), crosses the blood-brain barrier, thus complicating positron emission tomography-FDOPA (PET-FDOPA) data analysis. In previous reports the distribution volume (DV) of 3OMFD was constrained to unity. We have recently shown that the forward transport rate-constant of FDOPA ( KS1) and the cerebellum-to-plasma ratio ( Cb/ Cp), a measure for the DV of 3OMFD, are functions of plasma large neutral amino acid (LNAA) concentration. Given large interstudy and intersubject differences in plasma LNAA levels, variations in the DV of 3OMFD are significant. In this report, the authors propose a constraint on the DV of 3OMFD that accounts for these variations. Dynamic PET-FDOPA scans were performed on 12 squirrel monkeys and 12 vervet monkeys. Two sets of constraints were employed on the compartmental model—M1 or M2. In M1, the striatal DV of 3OMFD was constrained to unity; in M2, the striatal DV of 3OMFD was constrained to an estimate derived from the cerebellum. Striatal and cerebellar time-activity curves were fitted using FDOPA and 3OMFD plasma input functions. The estimate of KS1 and that of the compartmental FDOPA uptake-constant ( Ki), both obtained using M2, were adjusted to values corresponding to average LNAA levels. Finally, Ki was compared with the graphical uptake-constant ( PKi). With the use of constraint M2, intersubject variability of squirrel monkey kS3 and Ki was reduced by 45% and 53%, respectively; and for vervet monkeys, by 54% and 44%, respectively. Intersubject variability of Kl and Ki was further reduced after correction for variations in intersubject plasma LNAA levels (for squirrel monkeys, by 67% and 41%; for vervet monkeys, by 40% and 36%, respectively). Ki correlation to PKi was enhanced to identity. Finally, average cerebellar kC2 estimates were more than 2.5-fold higher than striatal kS2 estimates ( P < 0.0001). In modeling of PET-FDOPA data, it cannot be assumed that the DV of 3OMFD is unity. The cerebellar-derived constraint furnishes a reliable estimate for the DV of 3OMFD. Invoking the constraint and correcting for variations in plasma LNAA significantly reduced interstudy and intersubject variations in parameter estimates.

Amyloid plaques are highly heterogeneous in content, size, density, and macromolecular crowding, as they are composed of masses of fibrils and other cellular material. Given this target architecture, the aggregated microenvironment offers a unique imaging target for ligands and positron emission tomography (PET) molecular imaging probes (MIPs). In this work, we address how the heterogeneous microenvironment of a plaque and its evolution may affect the kinetic rate constant of PET MIPs. We argue that macromolecular crowding will result in anomalous diffusion within plaque regions. To account for anomalous diffusion within plaques, we propose a diffusion-limited ligand-receptor compartmental model. Given the current state of knowledge about the pathological progression of Alzheimer's disease (AD), the model's parameters may be a function of the pathological progression of AD, which could result in biased estimates of the true amyloid load. The bias may be partially overcome through evaluation in conjunction with other measures of AD progression including cerebral glucose metabolism rate, neuronal cell loss, and activated inflammatory presence.

Image-derived input functions (EDIF) are desirable for quantifying biological functions in mouse microPET studies. Due to difficulties in taking many blood samples from each mouse, conventional IDIF validation method of comparing blood samples with IDIF in a single animal is not applicable. A new approach that requires statistical testing on data of multiple animals has been conceived and investigated for IDIF validation. In this study, we evaluate and compare the power of 5 common statistical tests-Chi-square, sign test, signed-ranks, runs test, serial correlation-with the new approach for their ability to detect errors in IDIF. Computer simulation was used to simulate mouse FDG kinetics (60 min) and error-containing IDIF of various conditions. Deviations of IDIF from blood samples were examined with the 5 statistical tests. Results show that sign test, runs test and serial correlation do not have comparable power as the other two tests. The signed-ranks test generally had high statistical power, but was unable to detect errors that are random among animals or studies. Chi-square test could detect error in IDIF that was variable from study to study, but required accurate knowledge of noise variance. Combining signed-ranks test with Chi-square test is overall most sensitive for validation of IDIF.

The polymerization of beta-amyloid (A beta) peptides into fibrillary plaques is implicated, in part, in the pathogenesis of Alzheimer's disease. A beta molecular imaging probes (A beta-MIPs) have been introduced in an effort to quantify amyloid burden or load, in subjects afflicted with AD by invoking the classic PET receptor model for the quantitation of neuronal receptor density. In this communication, we explore conceptual differences between imaging the density of amyloid fibril polymers and neuronal receptors. We formulate a mathematical model for the polymerization of A beta with parameters that are mapped to biological modulators of fibrillogenesis and introduce a universal measure for amyloid load to accommodate various interactions of A beta-MIPs with fibrils. Subsequently, we hypothesize four A beta-MIPs and utilize the fibrillogenesis model to simulate PET tissue time activity curves (TACs). Given the unique nature of polymer growth and resulting PET TAC, the four probes report differing amyloid burdens for a given brain pathology, thus complicating the interpretation of PET images. In addition, we introduce the notion of an MIP's resolution, apparent maximal binding site concentration, optimal kinetic topology and its resolving power in characterizing the pathological progression of AD and the effectiveness of drug therapy. The concepts introduced in this work call for a new paradigm that goes beyond the classic parameters B(max) and K(D) to include binding characteristics to polymeric peptide aggregates such as amyloid fibrils, neurofibrillary tangles and prions.

Purpose Image-derived input functions are desirable for quantifying biological functions in dynamic mouse micro positron emission tomography (PET) studies, but the input function so derived needs to be validated. Conventional validation using serial blood samples is difficult in mice. We introduced the theoretical basis and used computer simulations to show the capability of a new approach that requires only a small number of blood samples per mouse but uses multiple animals. Procedures 2-Deoxy-2-[ 18 F]fluoro-D-glucose (FDG) kinetics (60 minutes) were simulated for 10 to 20 animals with three to six blood samples available per animal. Various amounts/types of noise/errors in the blood measurements were assumed, and different amounts/types of errors were added to the true input function to simulate image-derived input function. Deviations between blood samples and the derived input function were examined by statistical techniques to evaluate the capability of the approach for detecting the simulated errors in the derived input function. Results For a total of 60 blood samples and a 10% measurement noise, a 5% contaminating error in image-derived input function can be detected with a statistical power of ∼0.9 and with a 95% confidence. The power of the approach is directly related to the error magnitude in the image-derived input function, and is related to the total number of blood samples taken, but is inversely related to the measurement noise of the blood samples. Conclusion The new validation approach is expected to be useful for validating input functions derived with image-based methods in dynamic mouse microPET studies.

The authors used 2-(1-(6-[(2-[18F]fluoroethyl)(methyl)amino]-2-naphthyl)ethylidene)malononitrile ([18F]FDDNP), a hydrophobic radiofluorinated derivative of 2-(1-[6-(dimethylamino)-2-naphthyl]ethylidene)malononitrile (DDNP), in conjunction with positron emission tomography to determine the localization and load of neurofibrillary tangles (NFTs) and beta-amyloid senile plaques (APs) in the brains of living Alzheimer disease (AD) patients. Previous work illustrated the in vitro binding characteristics of [18F]FDDNP to synthetic beta-amyloid(1-40) fibrils and to NFTs and APs in human AD brain specimens. In the present study, greater accumulation and slower clearance was observed in AP- and NFT-dense brain areas and correlated with lower memory performance scores. The relative residence time of the probe in brain regions affected by AD was significantly greater in patients with AD (n=9) than in control subjects (n=7; p=0.0007). This noninvasive technique for monitoring AP and NFT development is expected to facilitate diagnostic assessment of patients with AD and assist in response-monitoring during experimental treatments.

Aromatic L-amino acid decarboxylase (AAAD) activity was examined in vivo with positron emission tomography (PET) using 6-[18F]fluoro-L-DOPA (FDOPA) in squirrel monkeys lesioned with graded doses of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). In vitro biochemical determinations of AAAD activity in caudate, putamen, substantia nigra, and nucleus accumbens were performed in the same animals to establish a direct comparison of in vivo and in vitro measurements. In vivo and in vitro AAAD activities in caudate/ putamen were substantially reduced in animals treated with the highest dose of MPTP (2.0 mg/kg). The percent change in the striatal FDOPA uptake (K(i)) and decarboxylation rate constant (k3) values resulting from MPTP treatment showed highly significant correlations with in vitro-determined AAAD activities. However, decarboxylase rates within individual animals presented as approximately 10-fold difference between in vivo and in vitro values. Lower in vivo k3 measurements may be attributed to several possibilities, including transport restrictions limiting substrate availability to AAAD within the neuron. In addition, reductions in AAAD activity in the substantia nigra did not parallel reductions in AAAD activity within the striatum, supporting the notion of a nonlinear relationship between nigrostriatal cell degeneration and terminal losses. This work further explores the role of AAAD in Parkinson's disease, a more important factor than previously thought.