Background
Alzheimer’s disease is a progressive, irreversible, and fatal disease for which accumulation of amyloid beta is thought to play a key role in pathogenesis. Aducanumab is a human monoclonal ...antibody directed against aggregated soluble and insoluble forms of amyloid beta.
Objectives
We evaluated the efficacy and safety of aducanumab in early Alzheimer’s disease.
Design
EMERGE and ENGAGE were two randomized, double-blind, placebo-controlled, global, phase 3 studies of aducanumab in patients with early Alzheimer’s disease.
Setting
These studies involved 348 sites in 20 countries.
Participants
Participants included 1638 (EMERGE) and 1647 (ENGAGE) patients (aged 50–85 years, confirmed amyloid pathology) who met clinical criteria for mild cognitive impairment due to Alzheimer's disease or mild Alzheimer's disease dementia, of which 1812 (55.2%) completed the study.
Intervention
Participants were randomly assigned 1:1:1 to receive aducanumab low dose (3 or 6 mg/kg target dose), high dose (10 mg/kg target dose), or placebo via IV infusion once every 4 weeks over 76 weeks.
Measurements
The primary outcome measure was change from baseline to week 78 on the Clinical Dementia Rating Sum of Boxes (CDR-SB), an integrated scale that assesses both function and cognition. Other measures included safety assessments; secondary and tertiary clinical outcomes that assessed cognition, function, and behavior; and biomarker endpoints.
Results
EMERGE and ENGAGE were halted based on futility analysis of data pooled from the first approximately 50% of enrolled patients; subsequent efficacy analyses included data from a larger data set collected up to futility declaration and followed prespecified statistical analyses. The primary endpoint was met in EMERGE (difference of -0.39 for high-dose aducanumab vs placebo 95% CI, -0.69 to -0.09; P=.012; 22% decrease) but not in ENGAGE (difference of 0.03, 95% CI, -0.26 to 0.33; P=.833; 2% increase). Results of biomarker substudies confirmed target engagement and dose-dependent reduction in markers of Alzheimer's disease pathophysiology. The most common adverse event was amyloid-related imaging abnormalities-edema.
Conclusions
Data from EMERGE demonstrated a statistically significant change across all four primary and secondary clinical endpoints. ENGAGE did not meet its primary or secondary endpoints. A dose-and time-dependent reduction in pathophysiological markers of Alzheimer’s disease was observed in both trials.
We present a parametrization of the observed enhancement in the transverse electron quasielastic (QE) response function for nucleons bound in carbon as a function of the square of the four momentum ...transfer (
Q
2
) in terms of a correction to the magnetic form factors of bound nucleons. The parametrization should also be applicable to the transverse cross section in neutrino scattering. If the transverse enhancement originates from meson exchange currents (MEC), then it is theoretically expected that any enhancement in the longitudinal or axial contributions is small. We present the predictions of the “Transverse Enhancement” model (which is based on electron scattering data only) for the
ν
μ
,
differential and total QE cross sections for nucleons bound in carbon. The
Q
2
dependence of the transverse enhancement is observed to resolve much of the long standing discrepancy in the QE total cross sections and differential distributions between low energy and high energy neutrino experiments on nuclear targets.
Genetics and pathology have proven to be an effective combination to identify an evolving and deepening landscape of pathways and potential therapeutic targets in neurodegenerative diseases. ...Initially this landscape appeared to be populated with distinct therapeutic targets but with potentially overlapping mechanisms in each neurodegenerative disease. Our understanding has expanded to recognize that multiple pathologies are common in neurodegenerative disease, and that there is considerable overlap in pathways and targets driving neurodegenerative diseases. This potentially opens the way for future treatments to be indicated by tissue pathology and genetic basis rather than clinical phenotype. The potential to treat neurodegenerative disease by addressing underlying pathophysiology is still in the early days and challenges remain, especially the likely need to address pathologies early in disease. This will require redefinition of diagnosis and the tools to enable earlier diagnosis.
Isocitrate dehydrogenase (IDH) is an enzyme required for the production of α-ketoglutarate from isocitrate. IDH3 generates the NADH used in the mitochondria for ATP production, and is a tetramer made ...up of two α, one β and one γ subunit. Loss-of-function and missense mutations in both
and
have previously been implicated in families exhibiting retinal degeneration. Using mouse models, we investigated the role of IDH3 in retinal disease and mitochondrial function. We identified mice with late-onset retinal degeneration in a screen of ageing mice carrying an ENU-induced mutation, E229K, in
Mice homozygous for this mutation exhibit signs of retinal stress, indicated by GFAP staining, as early as 3 months, but no other tissues appear to be affected. We produced a knockout of
and found that homozygous mice do not survive past early embryogenesis.
compound heterozygous mutants exhibit a more severe retinal degeneration compared with
homozygous mutants. Analysis of mitochondrial function in mutant cell lines highlighted a reduction in mitochondrial maximal respiration and reserve capacity levels in both
and
cells. Loss-of-function
mutants do not exhibit the same retinal degeneration phenotype, with no signs of retinal stress or reduction in mitochondrial respiration. It has previously been reported that the retina operates with a limited mitochondrial reserve capacity and we suggest that this, in combination with the reduced reserve capacity in mutants, explains the degenerative phenotype observed in
mutant mice.This article has an associated First Person interview with the first author of the paper.
We report the results of a search for ν(e) appearance in a ν(μ) beam in the MINOS long-baseline neutrino experiment. With an improved analysis and an increased exposure of 8.2 × 10(20) protons on the ...NuMI target at Fermilab, we find that 2 sin(2) (θ(23))sin(2)(2θ(13))<0.12(0.20) at 90% confidence level for δ = 0 and the normal (inverted) neutrino mass hierarchy, with a best-fit of 2sin(2) (θ(23))sin(2)(2θ(13)) = 0.041(-0.031)(+0.047) (0.079(-0.053) (+0.071)). The θ(13) = 0 hypothesis is disfavored by the MINOS data at the 89% confidence level.
For major congenital heart disease, the benefits of antenatal diagnosis on some post-natal measures have been suggested. However, findings have been inconclusive and focus on short term outcome ...measures alone with little data from a UK population. Our aim is to describe differences in reported outcomes for patients born with isolated Hypoplastic Left Heart Syndrome or Transposition of the Great Arteries in a UK population, following either antenatal or postnatal diagnosis.
Retrospective population-based study with case note review covering a 15 year period (1st January 1998 to 31st December 2012) in the British county of Leicestershire. Cases were identified from two local registers: the East Midlands and South Yorkshire Congenital Anomaly Register and a list of surgical patient held by the East Midlands Congenital Heart Centre.
In total 52 cases of Hypoplastic Left Heart Syndrome or Transposition of the Great Arteries were identified with 24 (46.2%) diagnosed antenatally. Maximum and minimum follow up was 181 and 16 months respectively. Median follow up was 83 months (IQR: 44-111). The risk of intubation in the postnatal period (OR: 4.64, 95% CI: 1.40 - 15.32) was greater in cases of Hypoplastic Left Heart Syndrome or Transposition of the Great Arteries diagnosed after birth when compared to those diagnosed antenatally. There was a non-significant increase in the risk of metabolic acidosis in the postnatal period (OR: 12.5, 95% CI: 0.64 - 245.46). No differences in mortality or long-term outcomes were demonstrated between antenatally and postnatally diagnosed cohorts.
These results confirm data from American and European populations that, for a British population, an antenatal diagnosis of a major congenital heart disease can have a favourable impact on some postnatal outcome measures. There appears to be no evidence that time of diagnosis impacts on long-term outcome measures.
We report measurements of oscillation parameters from ν(μ) and ν(μ) disappearance using beam and atmospheric data from MINOS. The data comprise exposures of 10.71×10(20) protons on target in the ...ν(μ)-dominated beam, 3.36×10(20) protons on target in the ν(μ)-enhanced beam, and 37.88 kton yr of atmospheric neutrinos. Assuming identical ν and ν oscillation parameters, we measure |Δm2| = (2.41(-0.10)(+0.09))×10(-3) eV2 and sin2(2θ) = 0.950(-0.036)(+0.035). Allowing independent ν and ν oscillations, we measure antineutrino parameters of |Δm2| = (2.50(-0.25)(+0.23))×10(-3) eV2 and sin2(2θ) = 0.97(-0.08)(+0.03), with minimal change to the neutrino parameters.
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