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To evaluate the potential superiority of donanemab vs. aducanumab on the percentage of participants with amyloid plaque clearance (≤24.1 Centiloids [CL]) at 6 months in patients with early symptomatic Alzheimer's disease (AD) in phase 3 TRAILBLAZER-ALZ-4 study. The amyloid cascade in AD involves the production and deposition of amyloid beta (Aβ) as an early and necessary event in the pathogenesis of AD.
Methods
Participants (n = 148) were randomized 1:1 to receive donanemab (700 mg IV Q4W [first 3 doses], then 1400 mg IV Q4W [subsequent doses]) or aducanumab (per USPI: 1 mg/kg IV Q4W [first 2 doses], 3 mg/kg IV Q4W [next 2 doses], 6 mg/kg IV Q4W [next 2 doses] and 10 mg/kg IV Q4W [subsequent doses]).
Results
Baseline demographics and characteristics were well-balanced across treatment arms (donanemab [N = 71], aducanumab [N = 69]). Twenty-seven donanemab-treated and 28 aducanumab-treated participants defined as having intermediate tau.
Upon assessment of florbetapir F18 PET scans (6 months), 37.9% donanemab-treated vs. 1.6% aducanumab-treated participants achieved amyloid clearance (p < 0.001). In the intermediate tau subpopulation, 38.5% donanemab-treated vs. 3.8% aducanumab-treated participants achieved amyloid clearance (p = 0.008).
Percent change in brain amyloid levels were −65.2%±3.9% (baseline: 98.29 ± 27.83 CL) and −17.0%±4.0% (baseline: 102.40 ± 35.49 CL) in donanemab and aducanumab arms, respectively (p < 0.001). In the intermediate tau subpopulation, percent change in brain amyloid levels were −63.9%±7.4% (baseline: 104.97 ± 25.68 CL) and −25.4%±7.8% (baseline: 102.23 ± 28.13 CL) in donanemab and aducanumab arms, respectively (p ≤ 0.001).
62.0% of donanemab-treated and 66.7% of aducanumab-treated participants reported an adverse event (AE), there were no serious AEs due to ARIA in donanemab arm and 1.4% serious AEs (one event) due to ARIA were reported in aducanumab arm.
Conclusion
This study provides the first active comparator data on amyloid plaque clearance in patients with early symptomatic AD. Significantly higher number of participants reached amyloid clearance and amyloid plaque reductions with donanemab vs. aducanumab at 6 months.
Previously presented at the Clinical Trials on Alzheimer's Disease - 15th Conference, 2022.
First published in 1973, this influential work discusses Einstein's General Theory of Relativity to show how two of its predictions arise: first, that the ultimate fate of many massive stars is to undergo gravitational collapse to form 'black holes'; and second, that there was a singularity in the past at the beginning of the universe. Starting with a precise formulation of the theory, including the necessary differential geometry, the authors discuss the significance of space-time curvature and examine the properties of a number of exact solutions of Einstein's field equations. They develop the theory of the causal structure of a general space-time, and use it to prove a number of theorems establishing the inevitability of singularities under certain conditions. A Foreword contributed by Abhay Ashtekar and a new Preface from George Ellis help put the volume into context of the developments in the field over the past fifty years.
In §8.1, we discuss the problem of defining singularities in spacetime. We adopt b-incompleteness as an indication that singular points have been cut out of spacetime, and characterize two ways in which b-incompleteness can be associated with some form of curvature singularity. In §8.2, four theorems are given to prove the existence of incompleteness under a wide variety of situations. In §8.3 we give Schmidt’s construction of the b-boundary which represents the singular points of spacetime. In §8.4 we prove that the singularities predicted by at least one of the the theorems cannot be just a discontinuity in the curvature tensor. We also show that there is not only one incomplete geodesic, but a three-parameter family of them. In §8.5 we discuss the situation in which the incomplete curves are totally or partially imprisoned in a compact region of spacetime, shown to be related to non-Hausdorff behaviour of the b-boundary. We show that in a generic spacetime, an observer travelling on one of these incomplete curves would experience infinite curvature forces. We also show that the kind of behaviour which occurs in Taub–NUT space cannot happen if there is some matter present.
In § 5.1 and § 5.2 we consider the simplest Lorentz metrics: those of constant curvature. The spatially isotropic and homogeneous cosmological models are described in §5.3, and their simplest anisotropic generalizations are discussed in § 5.4. It is shown that all such simple models will have a singular origin provided that A does not take large positive values. The spherically symmetric metrics which describe the field outside a massive charged or neutral body are examined in §5.5, and the axially symmetric metrics describing the field outside a special class of massive rotating bodies are described in §5.6. It is shown that some of the apparent singularities are simply due to a bad choice of coordinates. In §5.7 we describe the Godel universe and in §5.8 the Taub-NUT solutions. These probably do not represent the actual universe but they are of interest because of their pathological global properties. Finally some other exact solutions of interest are mentioned in §5.9.
The view of physics that is most generally accepted at the moment is that one can divide the discussion of the universe into two parts. First, there is the question of the local laws satisfied by the various physical fields. These are usually expressed in the form of differential equations. Secondly, there is the problem of the boundary conditions for these equations, and the global nature of their solutions. This involves thinking about the edge of spacetime in some sense. These two parts may not be independent. Indeed it has been held that the local laws are determined by the large scale structure of the universe. This view is generally connected with the name of Mach, and has more recently been developed by Dirac (1938), Sciama (1953), Dicke (1964), Hoyle and Narlikar (1964), and others. We shall adopt a less ambitious approach: we shall take the local physical laws that have been experimentally determined, and shall see what these laws imply about the large scale structure of the universe.
The expansion of the universe is in many ways similar to the collapse of a star, except that the sense of time is reversed. We shall show in this chapter that the conditions of theorems 2 and 3 seem to be satisfied, indicating that there was a singularity at the beginning of the present expansion phase of the universe, and we discuss the implications of spacetime singularities.
In §10.1 we show that past-directed closed trapped surfaces exist if the microwave background radiation in the universe has been partially thermalized by scattering, or alternatively if the Copernican assumption holds, i.e. we do not occupy a special position in the universe. In §10.2 we discuss the possible nature of the singularity and the breakdown of physical theory which occurs there.
In this chapter we consider the effect of spacetime curvature on families of timelike and null curves. These could represent flow lines of fluids or the histories of photons. In §4.1 and §4.2 we derive the formulae for the rate of change of vorticity, shear and expansion of such families of curves; the equation for the rate of change of expansion (Raychaudhuri’s equation) plays a central role in the proofs of the singularity theorems of chapter 8. In §4.3 we discuss the general inequalities on the energy–momentum tensor which imply that the gravitational effect of matter is always to tend to cause convergence of timelike and of null curves. A consequence of these energy conditions is, as is seen in §4.4, that conjugate or focal points will occur in families of non-rotating timelike or null geodesics in general spacetimes. In §4.5 it is shown that the existence of conjugate points implies the existence of variations of curves between two points which take a null geodesic into a timelike curve, or a timelike geodesic into a longer timelike curve.
In this chapter, we show that stars of more than about 1½ times the solar mass should collapse when they have exhausted their nuclear fuel. If the initial conditions are not too asymmetric, the conditions of theorem 2 should be satisfied and so there should be a singularity. This singularity is however probably hidden from the view of an external observer who sees only a ‘black hole’ where the star once was. We derive a number of properties of such black holes, and show that they probably settle down finally to a Kerr solution.
In §9.1 we discuss stellar collapse, showing how one would expect a closed trapped surface to form around any sufficiently large spherical star at a late stage in its evolution. In §9.2 we discuss the event horizon which seems likely to form around such a collapsing body. In §9.3 we consider the final stationary state to which the solution outside the horizon settles down. This seems to be likely to be one of the Kerr family of solutions. Assuming that this is the case, one can place certain limits on the amount of energy which can be extracted from such solutions.
In this chapter we give an outline of the Cauchy problem in general relativity and show that, given certain data on a space like three-surface there is a unique maximal future Cauchy development D+() and that the metric on a subset of D+() depends only on the initial data on J–() ∩. We also show that this dependence is continuous if has a compact closure in D+(). This discussion is included here because of its intrinsic interest, its use of some of the results of the previous chapter, and its demonstration that the Einstein field equations do indeed satisfy postulate (a) of §3.2 that signals can only be sent between points that can be joined by a non-spacelike curve.
In §7.1, we discuss the various difficulties and give a precise formulation of the problem. In §7.2 we introduce a global background metric ĝ to generalize the relation which holds between the Ricci tensor and the metric in each coordinate patch to a single relation which holds over the whole manifold. We impose four gauge conditions on the covariant derivatives of the physical metric g with respect to the background metric ĝ.
§6.1 deals with the question of the orientability of timelike and spacelike bases. In §6.2 basic causal relations are defined and the definition of a non-spacelike curve is extended from piecewise differentiable to continuous. The properties of the boundary of the future of a set are derived in §6.3. In §6.4a number of conditions which rule out violations or near violations of causality are discussed. The closely related concepts of Cauchy developments and global hyperbolicity are introduced in §6.5 and §6.6, and are used in §6.7 to prove the existence of non-spacelike geodesies of maximum length between certain pairs of points.
In §6.8 we describe the construction of Geroch, Kronheimer, and Penrose for attaching a causal boundary to spacetime. A particular example of such a boundary is provided by a class of asymptotically flat spacetimes which are studied in § 6.9
The spacetime structure is that of a manifold with a Lorentz metric and associated affine connection.
We introduce in §2.1 the concept of a manifold and in §2.2 vectors and tensors, which are the natural geometric objects defined on the manifold. A discussion of maps of manifolds in §2.3 leads to the definitions of the induced maps of tensors, and of sub-manifolds. The derivative of the induced maps defined by a vector field gives the Lie derivative defined in §2.4; another differential operation which depends only on the manifold structure is exterior differentiation, also defined in that section. This operation occurs in the generalized form of Stokes’ theorem.
The connection is introduced in §2.5, defining the covariant derivative and the curvature tensor. The connection is related to the metric on the manifold in §2.6; the curvature tensor is decomposed into the Weyl tensor and Ricci tensor, which are related to each other by the Bianchi identities.
The induced metric and connection on a hypersurface are discussed in §2.7, and the Gauss–Codacci relations are derived. The volume element defined by the metric is introduced in §2.8, and used to prove Gauss’ theorem.