Exploring a mathematical model for the kinetics of beta-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 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.

Serotonin 1A receptors in the living brain of Alzheimer's disease patients.

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.

Imaging beta-amyloid fibrils in Alzheimer's disease: a critical analysis through simulation of amyloid fibril polymerization.

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.

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-[18F]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.

Investigation of a new input function validation approach for dynamic mouse microPET studies.

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 approximately 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.

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.