Pittsburgh Compound B PET findings match histopathologic reports of beta-amyloid (Abeta) distribution in aging and dementia. Noninvasive longitudinal studies to better understand the role of amyloid deposition in the course of neurodegeneration and to determine if Abeta deposition in nondemented subjects is preclinical AD are now feasible. Our findings also suggest that Abeta may influence the development of dementia with Lewy bodies, and therefore strategies to reduce Abeta may benefit this condition.

Objective-Assess Aβ deposition longitudinally and explore its relationship with cognition and disease progression.Methods-Clinical follow-up was obtained 20 ± 3 months after [ 11 C]Pittsburgh compound B (PiB)-positron emission tomography in 206 subjects: 35 with dementia of the Alzheimer type (DAT), 65 with mild cognitive impairment (MCI), and 106 age-matched healthy controls (HCs). A second PiB scan was obtained at follow-up in 185 subjects and a third scan after 3 years in 57.Results-At baseline, 97% of DAT, 69% of MCI, and 31% of HC subjects showed high PiB retention. At 20-month follow-up, small but significant increases in PiB standardized uptake value Address correspondence to Dr Villemagne, Department of Nuclear Medicine and Centre for PET, Austin Health, 145 Studley Road, Heidelberg, Vic., 3084, Australia. villemagne@petnm.unimelb.edu.au. D.A. is Principle Investigator of the Australian Imaging, Biomarkers, and Lifestyle study of ageing.Additional Supporting Information can be found in the online version of this article. Potential Conflicts of InterestGE Healthcare holds a license agreement with the University of Pittsburgh based on the technology described in this article. W.E.K. and C.A.M. have received consultancy fees and royalties and have a grant pending from GE Healthcare. W.E.K. and C.A.M. are coinventors of PiB and, as such, have a financial interest in this license agreement. GE Healthcare provided no grant support for this study and had no role in the design or interpretation of results or preparation of the manuscript. All other authors have no conflicts of interest with this work, had full access to all of the data in the study, and take responsibility for the integrity of the data and the accuracy of the data analysis. NIH Public Access Author ManuscriptAnn Neurol. Author manuscript; available in PMC 2012 January 1. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript ratios were observed in the DAT and MCI groups, and in HCs with high PiB retention at baseline (5.7%, 2.1%, and 1.5%, respectively). Increases were associated with the number of apolipoprotein E ε4 alleles. There was a weak correlation between PiB increases and decline in cognition when all groups were combined. Progression to DAT occurred in 67% of MCI with high PiB versus 5% of those with low PiB, but 20% of the low PiB MCI subjects progressed to other dementias. Of the high PiB HCs, 16% developed MCI or DAT by 20 months and 25% by 3 years. One low PiB HC developed MCI.Interpretation-Aβ deposition increases slowly from cognitive normality to moderate severity DAT. Extensive Aβ deposition precedes cognitive impairment, and is associated with ApoE genotype and a higher risk of cognitive decline in HCs and progression from MCI to DAT over 1 to 2 years. However, cognitive decline is only weakly related to change in Aβ burden, suggesting that downstream factors have a more direct effect on symptom progression.In vivo amyloid imaging with positron emission tomography (PET) allows longitudinal study...

No abstract

No abstract

In this study, we have followed the fate of newly synthesized cc-and B-subunits of Na,K-ATPase in Xenopus oocytes injected with a and/or B cRNA to examine whether assembly of the two subunits is needed for a correct folding and/or for intracellular transport of Na,K-ATPase. Our data indicate that (1) assembly of a-and /?-subunits occurs at the level of the ER, (2) p-subunits are needed for the newly synthesized a-subunit to adopt a stable configuration and (3) a-and B-subunits mutually depend on each other to be transported out of the ER.

PET provides a noninvasive means to evaluate the functional integrity of the presynaptic monoaminergic system in the living human brain. Methods: In this study, a novel 18 F-labeled tetrabenazine derivative, 18 F-(1)fluoropropyldihydrotetrabenazine ( 18 F-AV-133), was used for the noninvasive assessment of the vesicular monoamine transporters type 2 (VMAT2) in 17 Parkinson disease (PD) patients and 6 healthy controls. The binding potential (BP) of 18 F-AV-133 was calculated using Logan graphical analysis. Voxel-based and volume-of-interest-based analyses of BP images were performed to examine brain regional reductions in VMAT2 density in PD. Results: VMAT2 BP was decreased by 81% in the posterior putamen, 70% in the anterior putamen, and 48% in the caudate nucleus of PD patients. Voxelbased analysis demonstrated VMAT2 reductions in the striatum and mid brain of PD patients. Furthermore, VMAT2 BPs in the caudate nuclei significantly correlated with the clinical severity of PD. Conclusion: These findings indicate that the novel 18 Flabeled ligand 18 F-AV-133 can sensitively detect monoaminergic terminal reductions in PD patients. Studies with 18 F-AV-133 may allow the presymptomatic identification of individuals with disorders characterized by degeneration of dopaminergic nigrostriatal afferents.

The reproductive cycle of female mosquitoes is activated by ingestion of blood from vertebrate hosts. Shortly after feeding, neurohormones are released from the brain neurosecretory system and stimulate the ovaries to secrete ecdysteroids, which are necessary for vitellogenesis by the fat body. Because bombyxins, which are insulin-like peptides, stimulate ecdysteriodgenesis in silkworm larvae, we tested porcine insulin and found that it activates ecdysteroidogenesis and protein synthesis in ovaries isolated from unfed mosquitoes. To further characterize the regulation of ecdysteroidogenesis in female mosquitoes, we cloned the mosquito insulin receptor (MIR) homologue from ovarian mRNA. The sequence of the extracellular domain shows moderate homologies with vertebrate and Drosophila insulin receptor homologues, as well as with the insulin receptor-related receptor, the latter being an "orphan" receptor with an unknown function. In the intracellular domain, high homologies are observed, particularly in those subdomains that are responsible for ATP binding and kinase activity. Northern blot analysis of MIR demonstrated a highly specific expression in ovaries, and cloning experiments indicated its presence in the brain. Recombinant MIR extracts from a baculovirus expression system contained high constitutive kinase activity in the presence of manganese or magnesium. Activation was independent of a ligand. SDS-gel analysis suggested that the recombinant receptor was not post-translationally processed into an alpha- and beta-subunit as was expected from a putative cleavage signal. Enzymatic properties of the proreceptor are presented: the Km for ATP was between 15 and 50 microM in the presence of a synthetic substrate: maximal kinase activity to 100-fold over basic activity was reached in the presence of 1 mM manganese. Stimulation of key oogenic processes by porcine insulin and identification of a MIR indicate that insulin-like neurohormones may have an important regulatory role in mosquito oogenesis.

The present study shows that differences in endogenous ANP activity in mice, resulting in chronic alterations in ABP are accompanied by directional changes in underlying cardiovascular sympathetic tone, and suggests that the chronic vasodilator effect of ANP is, at least partially, dependent on attenuation of vascular sympathetic tone, possibly at a prejunctional site(s).