An off-shell formulation for internally gauged D=5, N=2 supergravity from superconformal methods

We use the superconformal method to construct a new formulation for pure off-shell D=5, N=2 Poincar\'e supergravity and present its internal gauging. The main difference between the traditional formulation and our new formulation is the choice of the Dilaton Weyl Multiplet as the background Weyl Multiplet and the choice of a Linear compensating Multiplet. We do not introduce an external vector multiplet to gauge the theory, but instead use the internal vector of the Dilaton Weyl Multiplet. We show that the corresponding on-shell theory is Einstein-Maxwell supergravity. We believe that this gauging method can be applied in more complicated scenarios such as the inclusion of off-shell higher derivative invariants.Comment: 25 pages, 1 figure, v3: Version appeared in JHE

Symplectic gaugings and the field-antifield formalism

We give an example of how conventional gauging methods obstruct a systematic analysis of gauged supergravities. We discuss how the embedding tensor formalism deals with these problems and argue that the gauge algebra related to the embedding tensor formalism is soft, open and reducible. We connect the embedding tensor formalism to the field-antifield (or Batalin-Vilkovisky) formalism, which is the most general formulation known for gauge theories.Comment: Contribution to the Proceedings of the XVIth European Workshop on String Theory in Madrid (June 14-18, 2010), 10 page

Higher Derivative Extension of 6D Chiral Gauged Supergravity

Six-dimensional (1,0) supersymmetric gauged Einstein-Maxwell supergravity is extended by the inclusion of a supersymmetric Riemann tensor squared invariant. Both the original model as well as the Riemann tensor squared invariant are formulated off-shell and consequently the total action is off-shell invariant without modification of the supersymmetry transformation rules. In this formulation, superconformal techniques, in which the dilaton Weyl multiplet plays a crucial role, are used. It is found that the gauging of the U(1) R-symmetry in the presence of the higher-order derivative terms does not modify the positive exponential in the dilaton potential. Moreover, the supersymmetric Minkowski(4) x S^2 compactification of the original model, without the higher-order derivatives, is remarkably left intact. It is shown that the model also admits non-supersymmetric vacuum solutions that are direct product spaces involving de Sitter spacetimes and negative curvature internal spaces.Comment: 32 pages; typos corrected, footnote in conclusions section adde

Generalized gaugings and the field-antifield formalism

We discuss the algebra of general gauge theories that are described by the embedding tensor formalism. We compare the gauge transformations dependent and independent of an invariant action, and argue that the generic transformations lead to an infinitely reducible algebra. We connect the embedding tensor formalism to the field-antifield (or Batalin-Vilkovisky) formalism, which is the most general formulation known for general gauge theories and their quantization. The structure equations of the embedding tensor formalism are included in the master equation of the field-antifield formalism.Comment: 42 pages; v2: some clarifications and 1 reference added; version to be published in JHE

Tau pathology as determinant of changes in atrophy and cerebral blood flow: a multi-modal longitudinal imaging study

PURPOSE: Tau pathology is associated with concurrent atrophy and decreased cerebral blood flow (CBF) in Alzheimer's disease (AD), but less is known about their temporal relationships. Our aim was therefore to investigate the association of concurrent and longitudinal tau PET with longitudinal changes in atrophy and relative CBF. METHODS: We included 61 individuals from the Amsterdam Dementia Cohort (mean age 65.1 ± 7.5 years, 44% female, 57% amyloid-β positive [Aβ +], 26 cognitively impaired [CI]) who underwent dynamic [18F]flortaucipir PET and structural MRI at baseline and 25 ± 5 months follow-up. In addition, we included 86 individuals (68 CI) who only underwent baseline dynamic [18F]flortaucipir PET and MRI scans to increase power in our statistical models. We obtained [18F]flortaucipir PET binding potential (BPND) and R1 values reflecting tau load and relative CBF, respectively, and computed cortical thickness from the structural MRI scans using FreeSurfer. We assessed the regional associations between i) baseline and ii) annual change in tau PET BPND in Braak I, III/IV, and V/VI regions and cortical thickness or R1 in cortical gray matter regions (spanning the whole brain) over time using linear mixed models with random intercepts adjusted for age, sex, time between baseline and follow-up assessments, and baseline BPND in case of analyses with annual change as determinant. All analyses were performed in Aβ-  cognitively normal (CN) individuals and Aβ+  (CN and CI) individuals separately. RESULTS: In Aβ+ individuals, greater baseline Braak III/IV and V/VI tau PET binding was associated with faster cortical thinning in primarily frontotemporal regions. Annual changes in tau PET were not associated with cortical thinning over time in either Aβ+ or Aβ-  individuals. Baseline tau PET was not associated with longitudinal changes in relative CBF, but increases in Braak III/IV tau PET over time were associated with increases in parietal relative CBF over time in Aβ + individuals. CONCLUSION: We showed that higher tau load was related to accelerated cortical thinning, but not to decreases in relative CBF. Moreover, tau PET load at baseline was a stronger predictor of cortical thinning than change of tau PET signal

Genetic, vascular, and amyloid components of cerebral blood flow in a preclinical population

Aging-related cognitive decline can be accelerated by a combination of genetic factors, cardiovascular and cerebrovascular dysfunction, and amyloid-β burden. Whereas cerebral blood flow (CBF) has been studied as a potential early biomarker of cognitive decline, its normal variability in healthy elderly is less known. In this study, we investigated the contribution of genetic, vascular, and amyloid-β components of CBF in a cognitively unimpaired (CU) population of monozygotic older twins. We included 134 participants who underwent arterial spin labeling (ASL) MRI and [18F]flutemetamol amyloid-PET imaging at baseline and after a four-year follow-up. Generalized estimating equations were used to investigate the associations of amyloid burden and white matter hyperintensities with CBF. We showed that, in CU individuals, CBF: 1) has a genetic component, as within-pair similarities in CBF values were moderate and significant (ICC > 0.40); 2) is negatively associated with cerebrovascular damage; and 3) is positively associated with the interaction between cardiovascular risk scores and early amyloid-β burden, which may reflect a vascular compensatory response of CBF to early amyloid-β accumulation. These findings encourage future studies to account for multiple interactions with CBF in disease trajectory analyses

Performance of a [18F]Flortaucipir PET Visual Read Method Across the Alzheimer Disease Continuum and in Dementia With Lewy Bodies

Background and Objectives: Recently, the US Food and Drug Administration approved the tau-binding radiotracer [18F]flortaucipir and an accompanying visual read method to support the diagnostic process in cognitively impaired patients assessed for Alzheimer disease (AD). Studies evaluating this visual read method are limited. In this study, we evaluated the performance of the visual read method in participants along the AD continuum and dementia with Lewy bodies (DLB) by determining its reliability, accordance with semiquantitative analyses, and associations with clinically relevant variables. // Methods: We included participants who underwent tau-PET at Amsterdam University Medical Center. A subset underwent follow-up tau-PET. Two trained nuclear medicine physicians visually assessed all scans. Inter-reader agreement was calculated using Cohen κ. To examine the concordance of visual read tau positivity with semiquantification, we defined standardized uptake value ratio (SUVr) positivity using different threshold approaches. To evaluate the prognostic value of tau-PET visual read, we performed linear mixed models with longitudinal Mini-Mental State Examination (MMSE). // Results: We included 263 participants (mean age 68.5 years, 45.6% female), including 147 cognitively unimpaired (CU) participants, 97 amyloid-positive participants with mild cognitive impairment or AD dementia (AD), and 19 participants with DLB. The visual read inter-reader agreement was excellent (κ = 0.95, CI 0.91–0.99). None of the amyloid-negative CU participants (0/92 [0%]) and 1 amyloid-negative participant with DLB (1/12 [8.3%]) were tau-positive. Among amyloid-positive participants, 13 CU participants (13/52 [25.0%]), 85 with AD (85/97 [87.6%]), and 3 with DLB (3/7 [42.9%]) were tau-positive. Two-year follow-up visual read status was identical to baseline. Tau-PET visual read corresponded strongly to SUVr status, with up to 90.4% concordance. Visual read tau positivity was associated with a decline on the MMSE in CU participants (β = −0.52, CI −0.74 to −0.30, p < 0.001) and participants with AD (β = −0.30, CI −0.58 to −0.02, p = 0.04). // Discussion: The excellent inter-reader agreement, strong correspondence with SUVr, and longitudinal stability indicate that the visual read method is reliable and robust, supporting clinical application. Furthermore, visual read tau positivity was associated with prospective cognitive decline, highlighting its additional prognostic potential. Future studies in unselected cohorts are needed for a better generalizability to the clinical population. // Classification of Evidence: This study provides Class II evidence that [18F]flortaucipir visual read accurately distinguishes patients with low tau-tracer binding from those with high tau-tracer binding and is associated with amyloid positivity and cognitive decline. // Glossary: Aβ=β-amyloid; AD=Alzheimer disease; CU=cognitively unimpaired; DLB=dementia with Lewy bodies; US FDA=US Food and Drug Administration; GMM=Gaussian mixture model; LMM=linear mixed model; MCI=mild cognitive impairment; MMSE=Mini-Mental State Examination; OR=odds ratio; ROI=region of interest; SCD=subjective cognitive decline; SUVr=standardized uptake value ratio

Genetically identical twin-pair difference models support the amyloid cascade hypothesis

The amyloid cascade hypothesis has strongly impacted the Alzheimer's disease research agenda and clinical trial designs over the past decades, but precisely how amyloid-β pathology initiates the aggregation of neocortical tau remains unclear. We cannot exclude the possibility of a shared upstream process driving both amyloid-β and tau in an independent manner instead of there being a causal relationship between amyloid-β and tau. Here, we tested the premise that if a causal relationship exists, then exposure should be associated with outcome both at the individual-level as well as within identical twin-pairs, who are strongly matched on genetic, demographic and shared environmental background. Specifically, we tested associations between longitudinal amyloid-β PET and cross-sectional tau-PET, neurodegeneration and cognitive decline using genetically identical twin-pair difference models, which provide the unique opportunity of ruling out genetic and shared environmental effects as potential confounders in an association. We included 78 cognitively unimpaired identical twins with [18F]flutemetamol (amyloid-β)-PET, [18F]flortaucipir (tau)-PET, MRI (hippocampal volume), and cognitive data (composite memory). Associations between each modality were tested at the individual-level using generalized estimating equation models, and within identical twin-pairs using within-pair difference models. Mediation analyses were performed to test for directionality in the associations as suggested by the amyloid cascade hypothesis. At the individual-level, we observed moderate-to-strong associations between amyloid-β, tau, neurodegeneration and cognition. The within-pair difference models replicated results observed at the individual-level with comparably strong effect sizes. Within-pair differences in amyloid-β were strongly associated with within-pair differences in tau (β=0.68, p < 0.001), and moderately associated with within-pair differences in hippocampal volume (β=-0.37, p = 0.03) and memory functioning (β=-0.57, p < 0.001). Within-pair differences in tau were moderately associated with within-pair differences in hippocampal volume (β=-0.53, p < 0.001) and strongly associated with within-pair differences in memory functioning (β=-0.68, p < 0.001). Mediation analyses showed that of the total twin-difference effect of amyloid-β on memory functioning, the proportion mediated through pathways including tau and hippocampal volume was 69.9%, which was largely attributable to the pathway leading from amyloid-β to tau to memory functioning (proportion mediated: 51.6%). Our results indicate that associations between amyloid-β, tau, neurodegeneration and cognition are unbiased by (genetic) confounding. Furthermore, effects of amyloid-β on neurodegeneration and cognitive decline were fully mediated by tau. These novel findings in this unique sample of identical twins are compatible with the amyloid cascade hypothesis and thereby provide important new knowledge for clinical trial designs

Higher derivative supergravities from superconformal methods

The most promising candidate for a consistent theory of quantum gravity is superstring theory. The low energy effective physics of string theory is described by supergravity. In this thesis we review the superconformal construction of supergravity and focus on the construction of supergravity Lagrangians containing higher derivative terms.In the first part of the thesis we introduce supersymmetry, supergravity and the superconformal method. Particular emphasis is put on the minimal D=5 and D=6 settings. We construct off-shell formulations of the pure minimal D=5 and D=6 supergravities and explain how 5 dimensional gauged Einstein-Maxwell theories and the 6 dimensional Salam-Sezgin model, which is 6 dimensional gauged Einstein-Maxwell supergravity, can be obtained from superconformal methods. We discuss to which settings the superconformal method is restricted and distinguish between settings with not more than 8 supersymmetries for which off-shell formulations exist and settings with 16 supersymmetries for which only on-shell formulations exist.In the second part we focus on higher derivative deformations of supergravity theories. An overview is given of the different superconformal higher derivative invariants that have been constructed in the literature. As an example we consider the deformation of the Salam-Sezgin model by a supersymmetric completion of the Riemann tensor squared. We explain the difficulties related to the construction of superconformal higher derivative invariants for theories with 16 supersymmetries for which only on-shell formulations exist. We look for new ways of constructing such invariants based on the worldvolume action of D-branes.1. Introduction 2. Supersymmetry 3. Supergravity from the Noether method: focus on D=5 and D=6 4. Supergravity from superconformal methods: focus on D=5 and D=6 5. Deforming the pure theories: Einstein-Maxwell theories 6. Deforming the pure theories: higher derivative terms 7. Higher derivative extension of gauged minimal D=6 supergravity 8. Dirac-Born-Infeld-Volkov-Akulov and deformation of supersymmetry 9. Epilogue A. Notations and conventions B. Gauge theories C. Dp-branes D. Vp-branes Bibliographynrpages: 230status: publishe