Kooresh Shoghi-Jadid

Localization of neurofibrillary tangles and beta-amyloid plaques in the brains of living patients with Alzheimer disease.

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.

Nigrostriatal reduction of aromatic L-amino acid decarboxylase activity in MPTP-treated squirrel monkeys : In vivo and in vitro investigations

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 (Ki) 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 ~ 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 Parkinsons disease, a more important factor than previously thought.

Exploring a Mathematical Model for the Kinetics of β-Amyloid Molecular Imaging Probes through a Critical Analysis of Plaque Pathology

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 Alzheimers disease (AD), the models 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.

Striatal Kinetic Modeling of FDOPA with a Cerebellar-Derived Constraint on the Distribution Volume of 3OMFD: A PET Investigation using Non-Human Primates

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.

First-pass angiography in mice using FDG-PET: a simple method of deriving the cardiovascular transit time without the need of region-of-interest drawing

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.

Statistical tests for discriminating inaccurate input functions in dynamic mouse microPET studies

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.