Effects of Amyloid-β Deposition on Mitochondrial Complex I Activity in Brain: A PET Study in Monkeys

This chapter discusses the capabilities of positron emission tomography (PET) imaging for the diagnosis of Alzheimer’s disease (AD) with deposition of amyloid-β (Aβ). We conducted a PET scan using 18F-2-tert-butyl-4-chloro-5-{6-[2-(2-fluoroethoxy)-ethoxy]-pyridin-3-ylmethoxy}-2H-pyridazin-3-one (18F-BCPP-EF), a novel PET probe for mitochondrial complex I (MC-I) activity, in young and aged monkeys to demonstrate the normal aging effects on MC-I activity in the brain. The results revealed an age-related impairment of MC-I activity in the brain. Then, we conducted PET scan using 11C-PIB to detect the Aβ deposition in the some parts, not all, of the brains of some part of aged monkeys. For further assessments, PET scans using 11C-PIB for Aβ, 11C-DPA-713 for inflammation, 18F-fluoro-2-deoxy-D-glucose (18F-FDG) for regional cerebral metabolic rate of glucose (rCMRglc), and 18F-BCPP-EF for MC-I were performed in aged animals. When 18F-BCPP-EF uptake is plotted against 11C-PIB uptake in the cerebral cortical regions, it showed a significant negative correlation between them. Plotting of 11C-DPA-713 uptake against 11C-PIB resulted in a significant positive correlation. In contrast, plotting of rCMRglc against 11C-PIB did not reach a statistically significant level. Taken together, these results strongly suggested that 18F-BCPP-EF could discriminate the neuronally damaged areas with neuroinflammation where 18F-FDG could not, owing to its high uptake into the activated microglia

PET Imaging of Mitochondrial Function in the Living Brain

In the last two and half decades, we have conducted research on brain functional imaging in nonhuman primates using animal positron emission tomography (PET) scanners with high spatial resolution. We recently designed and synthesized the novel PET probe [18F]BCPP-EF to quantitatively image mitochondria complex-I (MC-I) activity in the living brain. Brain MC-I activity, measured using [18F]BCPP-EF, was significantly lower in aged monkeys than that in young animals, while no significant reduction was observed in SV2A activity, a synaptic-specific parameter that was measured using [11C]UCB-J. Some aged monkeys exhibited increased amyloid-β deposition in the brain, measured using [11C]PiB, which induced neuroinflammation. A positive correlation was noted with neuroinflammation, measured using [11C]DPA-713 and a negative correlation with MC-I activity. Furthermore, a monkey model of Parkinson’s disease prepared by the chronic administration of MPTP revealed suppressed MC-I activity not only in the nigrostriatal dopamine pathway, measured using [11C]PE2I and [11C]6MemTyr, but also in cortical serotonergic neurons, measured using [11C]DASB. This review introduces the translational application of a novel PET probe for noninvasive MC-I imaging from preclinical to clinical PET measurements

Possible role of immune surveillance at the initial phase of metastasis produced by B16BL6 melanoma cells

AbstractThe relationship among the real-time trafficking of lung metastatic B16BL6 cells, metastatic potential, and the injected number of the cells was examined, since the smaller the number of tumor cells injected, the more clearly the immune defense may be observed. When 1×106 or 1×105 B16BL6 cells were injected into mice via the tail vein, both numbers of cells accumulated in the lung at a similar rate: there was an approximately 10-fold difference in the number of accumulated cells between the two doses. Elimination from the lung was not dependent on the cell number but on the proportion of accumulated cells. However, the injection of 1×104 cells resulted in lung accumulation less than one-tenth of that obtained with 1×105 cell injection. Metastasis was observed when 1×105 or 1×106 B16BL6 cells were injected, but not after injection of 1×104 cells. To clarify the roles of the immune defense system at the initial phase of metastasis, we challenged macrophage-depleted mice with 1×104 tumor cells. Treatment of mice with 2-chloroadenosine prior to the tumor cell challenge cancelled the suppression of not only metastasis but also the lung accumulation. Furthermore, the administration of 2-chloroadenosine following the tumor cell challenge had little effect on the metastatic potential. These results suggest that the immune surveillance whose action was obvious at the low dose of challenged tumor cells functions strongly at the initial phase but not at the advanced stages of the metastatic process, and that macrophages play an important role in the suppression of metastasis

Polar surface engineering in ultra-thin MgO(111)/Ag(111) -- possibility of metal-insulator transition and magnetism

A recent report [Kiguchi {\it et al.}, Phys. Rev. B {\bf 68}, 115402 (2003)] that the (111) surface of 5 MgO layers grown epitaxially on Ag(111) becomes metallic to reduce the electric dipole moment raises a question of what will happen when we have fewer MgO layers. Here we have revealed, first experimentally with electron energy-loss spectroscopy, that MgO(111) remains metallic even when one-layer thick, and theoretically with the density functional theory that the metallization should depend on the nature of the substrate. We further show, with a spin-density functional calculation, that a ferromagnetic instability may be expected for thicker films.Comment: 5 pages, 7 figure

In Vivo Evaluation of α7 Nicotinic Acetylcholine Receptor Agonists [11C]A-582941 and [11C]A-844606 in Mice and Conscious Monkeys

BACKGROUND: The alpha7 nicotinic acetylcholine receptors (nAChRs) play an important role in the pathophysiology of neuropsychiatric diseases such as schizophrenia and Alzheimer's disease. The goal of this study was to evaluate the two carbon-11-labeled alpha7 nAChR agonists [(11)C]A-582941 and [(11)C]A-844606 for their potential as novel positron emission tomography (PET) tracers. METHODOLOGY/PRINCIPAL FINDINGS: The two tracers were synthesized by methylation of the corresponding desmethyl precursors using [(11)C]methyl triflate. Effects of receptor blockade in mice were determined by coinjection of either tracer along with a carrier or an excess amount of a selective alpha7 nAChR agonist (SSR180711). Metabolic stability was investigated using radio-HPLC. Dynamic PET scans were performed in conscious monkeys with/without SSR180711-treatment. [(11)C]A-582941 and [(11)C]A-844606 showed high uptake in the mouse brain. Most radioactive compounds in the brain were detected as an unchanged form. However, regional selectivity and selective receptor blockade were not clearly observed for either compound in the mouse brain. On the other hand, the total distribution volume of [(11)C]A-582941 and [(11)C]A-844606 was high in the hippocampus and thalamus but low in the cerebellum in the conscious monkey brain, and reduced by pretreatment with SSR180711. CONCLUSIONS/SIGNIFICANCE: A nonhuman primate study suggests that [(11)C]A-582941 and [(11)C]A-844606 would be potential PET ligands for imaging alpha7 nAChRs in the human brain

The posterior parietal cortex contributes to visuomotor processing for saccades in blindsight macaques

Patients with damage to the primary visual cortex (V1) lose visual awareness, yet retain the ability to perform visuomotor tasks, which is called "blindsight." To understand the neural mechanisms underlying this residual visuomotor function, we studied a non-human primate model of blindsight with a unilateral lesion of V1 using various oculomotor tasks. Functional brain imaging by positron emission tomography showed a significant change after V1 lesion in saccade-related visuomotor activity in the intraparietal sulcus area in the ipsi- and contralesional posterior parietal cortex. Single unit recordings in the lateral bank of the intraparietal sulcus (lbIPS) showed visual responses to targets in the contralateral visual field on both hemispheres. Injection of muscimol into the ipsi- or contralesional lbIPSs significantly impaired saccades to targets in the V1 lesion-affected visual field, differently from previous reports in intact animals. These results indicate that the bilateral lbIPSs contribute to visuomotor function in blindsight

Ferromagnetism in a Hubbard model for an atomic quantum wire: a realization of flat-band magnetism from even-membered rings

We have examined a Hubbard model on a chain of squares, which was proposed by Yajima et al as a model of an atomic quantum wire As/Si(100), to show that the flat-band ferromagnetism according to a kind of Mielke-Tasaki mechanism should be realized for an appropriate band filling in such a non-frustrated lattice. Reflecting the fact that the flat band is not a bottom one, the ferromagnetism vanishes, rather than intensified, as the Hubbard U is increased. The exact diagonalization method is used to show that the critical value of U is in a realistic range. We also discussed the robustness of the magnetism against the degradation of the flatness of the band.Comment: misleading terms and expressions are corrected, 4 pages, RevTex, 5 figures in Postscript, to be published in Phys. Rev. B (rapid communication