Amyloid and tau pathology associations with personality traits, neuropsychiatric symptoms, and cognitive lifestyle in the preclinical phases of sporadic and autosomal dominant Alzheimer’s disease

Background Major prevention trials for Alzheimer’s disease (AD) are now focusing on multidomain lifestyle interventions. However, the exact combination of behavioral factors related to AD pathology remains unclear. In 2 cohorts of cognitively unimpaired individuals at risk of AD, we examined which combinations of personality traits, neuropsychiatric symptoms, and cognitive lifestyle (years of education or lifetime cognitive activity) related to the pathological hallmarks of AD, amyloid-β, and tau deposits. Methods A total of 115 older adults with a parental or multiple-sibling family history of sporadic AD (PREVENT-AD [PRe-symptomatic EValuation of Experimental or Novel Treatments for AD] cohort) underwent amyloid and tau positron emission tomography and answered several questionnaires related to behavioral attributes. Separately, we studied 117 mutation carriers from the DIAN (Dominant Inherited Alzheimer Network) study group cohort with amyloid positron emission tomography and behavioral data. Using partial least squares analysis, we identified latent variables relating amyloid or tau pathology with combinations of personality traits, neuropsychiatric symptoms, and cognitive lifestyle. Results In PREVENT-AD, lower neuroticism, neuropsychiatric burden, and higher education were associated with less amyloid deposition (p = .014). Lower neuroticism and neuropsychiatric features, along with higher measures of openness and extraversion, were related to less tau deposition (p = .006). In DIAN, lower neuropsychiatric burden and higher education were also associated with less amyloid (p = .005). The combination of these factors accounted for up to 14% of AD pathology. Conclusions In the preclinical phase of both sporadic and autosomal dominant AD, multiple behavioral features were associated with AD pathology. These results may suggest potential pathways by which multidomain interventions might help delay AD onset or progression

Time-resolved fluorescence studies of enhanced green fluorescent protein and the molecular dynamics of 3- Phosphoinositide Dependent Protein Kinase 1

Fluorescent proteins (FPs), particularly Enhanced Green Fluorescent Protein (EGFP), are essential tools in the study of intact biological systems. Whilst the photophysics of its progenitor, GFP, have been investigated extensively, far fewer studies of EGFP have been made. In this thesis, a full characterisation of EGFP excited state photophysics by singleand two-photon time-resolved fluorescence lifetime and anisotropy is presented. Furthermore, the two-photon transition tensor, determined by absorption and initial anisotropies, is shown to be dominated by a single element. The two-photon excited state of EGFP was subject to Stimulated Emission Depletion (STED), revealing the stimulated emission cross section, the ground state relaxation time and the time evolution of the higher order distribution moments to which anisotropy is not sensitive. The strong adherence to theoretical Debye diffusion reinforced the conclusions of the two-photon structure model, and showed EGFP to be an excellent molecule for the future development of STED. In addition, these studies provided a sound basis on which to employ single- and two-photon FRET in vivo and in vitro. Cell behaviour is governed by the transduction of molecular signals from the extracellular environment to intracellular compartments. At the centre of the PI 3-kinase signalling pathway is PDK1, a Serine/Threonine kinase, which phosphorylates numerous important downstream targets including Protein Kinase B (PKB). To date however, the regulatory mechanisms governing the behaviour of this protein remain poorly understood. Timeresolved fluorescence lifetime imaging microscopy (FLIM) was employed with FP tagged PDK1 to investigate dynamic interactions in intact cells in situ and in vivo. PDK1 was shown to dimerise in a manner dependent on PI 3-kinase activity and PDK1 PH domain lipid binding. To detail the structure of the observed intermolecular interaction, recombinant FP labelled PDK1 was produced with insect cells. Measurement of the rise in acceptor fluorescence during FRET in vitro indicated the PDK1 dimer pair exists in an antiparallel arrangement. These results provide the first insight on the structure of the dimer and demonstrate that the generation of 3-phosphorylated lipids is required for its formation

Mechanical feedback between membrane tension and dynamics

10.1016/j.tcb.2012.07.005Trends in Cell Biology2210527-535TCBI

Plasma membrane tension orchestrates membrane trafficking, cytoskeletal remodeling, and biochemical signaling during phagocytosis

10.1073/pnas.1301766110Proceedings of the National Academy of Sciences of the United States of America1102911875-11880PNAS

Restricted state selection in fluorescent protein Förster resonance energy transfer

10.1021/ja312230bJournal of the American Chemical Society135217883-7890JACS

A note on weighted likelihood and Jeffreys modal estimation of proficiency levels in polytomous item response models

Warm (1989) established the equivalence between the so-called Jeffreys modal and the weighted likelihood estimators of proficiency level with some dichotomous item response models. The purpose of this note is to extend this result to polytomous item response models. First, a general condition is derived to ensure the perfect equivalence between these two estimators. Second, it is shown that this condition is fulfilled by two broad classes of polytomous models including, among others, the partial credit, rating scale, graded response and nominal response models