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Head-to-head comparison of 11C-PiB and 18F-AZD4694 (NAV4694) for β-amyloid imaging in aging and dementia.
Rowe, CC, Pejoska, S, Mulligan, RS, Jones, G, Chan, JG, Svensson, S, Cselényi, Z, Masters, CL, Villemagne, VL
Journal of nuclear medicine : official publication, Society of Nuclear Medicine. 2013;(6):880-6
Abstract
UNLABELLED (11)C-Pittsburgh compound-B ((11)C-PiB) is the benchmark radiotracer for imaging of β-amyloid (Aβ) plaque in Alzheimer disease (AD). (18)F-labeled Aβ tracers subsequently developed for clinical use show higher nonspecific white matter binding and, in some cases, lower cortical binding in AD that could lead to less accurate interpretation of scans. We compared the cortical and white matter binding of a new (18)F-labeled Aβ tracer, (18)F-AZD4694 (recently renamed NAV4694), with (11)C-PiB in the same subjects. METHODS Forty-five participants underwent PET imaging with (11)C-PiB and (18)F-AZD4694 (25 healthy elderly controls [HCs], 10 subjects with mild cognitive impairment, 7 subjects with probable AD, and 3 subjects with probable frontotemporal dementia). Images were coregistered so that region-of-interest placement was identical on both scans, and standardized uptake value ratios (SUVRs) using the cerebellar cortex as a reference region were calculated between 40 and 70 min after injection for both tracers. RESULTS (18)F-AZD4694 showed reversible binding kinetics similar to (11)C-PiB, reaching an apparent steady state at 50 min after injection. Both radiotracers showed a similar dynamic range of neocortical SUVR (1.1-3.3 and 1.0-3.2 SUVR for (11)C-PiB and (18)F-AZD4694, respectively) and identical low nonspecific white matter binding, with frontal cortex-to-white matter ratios of 0.7 ± 0.2 and 1.3 ± 0.2 for both radiotracers in HCs and AD subjects, respectively. There was an excellent linear correlation between (11)C-PiB and (18)F-AZD4694 neocortical SUVR (slope of 0.95, r = 0.99, P < 0.0001). CONCLUSION (18)F-AZD4694 displays imaging characteristics nearly identical to those of (11)C-PiB. The low white matter and high cortical binding in AD indicate that this tracer is well suited to both clinical and research use.
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Dimer formation enhances structural differences between amyloid β-protein (1-40) and (1-42): an explicit-solvent molecular dynamics study.
Barz, B, Urbanc, B
PloS one. 2012;(4):e34345
Abstract
Amyloid β-protein (Aβ) is central to the pathology of Alzheimer's disease. A 5% difference in the primary structure of the two predominant alloforms, Aβ(1-40) and Aβ(1-42), results in distinct assembly pathways and toxicity properties. Discrete molecular dynamics (DMD) studies of Aβ(1-40) and Aβ(1-42) assembly resulted in alloform-specific oligomer size distributions consistent with experimental findings. Here, a large ensemble of DMD-derived Aβ(1-40) and Aβ(1-42) monomers and dimers was subjected to fully atomistic molecular dynamics (MD) simulations using the OPLS-AA force field combined with two water models, SPCE and TIP3P. The resulting all-atom conformations were slightly larger, less compact, had similar turn and lower β-strand propensities than those predicted by DMD. Fully atomistic Aβ(1-40) and Aβ(1-42) monomers populated qualitatively similar free energy landscapes. In contrast, the free energy landscape of Aβ(1-42) dimers indicated a larger conformational variability in comparison to that of Aβ(1-40) dimers. Aβ(1-42) dimers were characterized by an increased flexibility in the N-terminal region D1-R5 and a larger solvent exposure of charged amino acids relative to Aβ(1-40) dimers. Of the three positively charged amino acids, R5 was the most and K16 the least involved in salt bridge formation. This result was independent of the water model, alloform, and assembly state. Overall, salt bridge propensities increased upon dimer formation. An exception was the salt bridge propensity of K28, which decreased upon formation of Aβ(1-42) dimers and was significantly lower than in Aβ(1-40) dimers. The potential relevance of the three positively charged amino acids in mediating the Aβ oligomer toxicity is discussed in the light of available experimental data.
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NMR investigations of amyloid-β peptide interactions with propofol at clinically relevant concentrations with and without aqueous halothane solution.
Mandal, PK, Bhavesh, NS, Chauhan, VS, Fodale, V
Journal of Alzheimer's disease : JAD. 2010;(4):1303-9
Abstract
Oligomerization of amyloid-β peptide (Aβ) is an important stage in Alzheimer's disease. Recently, it has been shown that in an experimental model, smaller sized anesthetics (e.g., isoflurane, desflurane, etc.) induce Aβ oligomerization. Using state-of-the-art solution nuclear magnetic resonance, spectroscopic studies on Aβ interaction with propofol indicated that propofol does not interact with the G29, A30, and I31 residues of Aβ peptide at a clinically relevant concentration (0.083 mM), and no Aβ oligomerization was observed after 69 days. However, Aβ oligomerization was observed when treated with propofol (clinically relevant concentration) coadministered with aqueous halothane solution. Furthermore, dose dependence studies at various propofol concentrations (0.32 mM, 2.07 mM, and 53.4 mM) indicate the effect of propofol concentration on Aβ oligomerization revealing the hydrophobic nature of interactions between propofol with these critical residues (G29, A30, and I31). These experimental findings reaffirm that smaller molecular sized anesthetics (e.g., halothane) do play a leading role in Aβ oligomerization.
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Plasma beta carotene in Alzheimer's disease. Association with cerebrospinal fluid beta-amyloid 1-40, (Abeta40), beta-amyloid 1-42 (Abeta42) and total Tau.
Stuerenburg, HJ, Ganzer, S, Müller-Thomsen, T
Neuro endocrinology letters. 2005;(6):696-8
Abstract
We studied the plasma beta carotene concentrations in 40 Alzheimer's disease patients and the association with cerebrospinal fluid beta-amyloid 1-40, (Abeta40), cerebrospinal fluid beta-amyloid 1-42 (Abeta42) and cerebrospinal fluid total Tau. We found that patients with plasma beta carotene levels below the 25th percentile had 55% reduced ratios of Abeta40/Tau and 51% reduced ratios of Abeta 40/Abeta 42 compared with patients in the highest quartile. Mean Tau concentrations in the lowest quartile of plasma beta-carotene levels were 74% higher compared with the highest quartile of plasma beta-carotene levels. Thus, we could demonstrate an statistically significant association between beta carotene levels in plasma and neurochemical markers in the cerebrospinal fluid of Alzheimer's disease patients.
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Correlation of statin-increased platelet APP ratios and reduced blood lipids in AD patients.
Baskin, F, Rosenberg, RN, Fang, X, Hynan, LS, Moore, CB, Weiner, M, Vega, GL
Neurology. 2003;(12):2006-7
Abstract
Platelets, like neurons, contain 120- to 130- and 110-kd amyloid precursor proteins (APPs). Their ratio is reduced in AD, further reductions correlating with reduced Mini-Mental Status Examination scores [r(11) = 0.69, p < 0.05]. As statins alter APP processing, platelet APPs were analyzed in patients with AD given anticholesterol drugs for 6 weeks. APP ratios increased [t(37) = -3.888, p = 0.0004], proportionally with reduced cholesterol [r(36) = -0.45, p = 0.005]. Longer trials may reveal slowed cognitive loss, validating this index.