The relative efficiency of time-to-progression and continuous measures of cognition in presymptomatic Alzheimer's disease.

IntroductionClinical trials on preclinical Alzheimer's disease are challenging because of the slow rate of disease progression. We use a simulation study to demonstrate that models of repeated cognitive assessments detect treatment effects more efficiently than models of time to progression.MethodsMultivariate continuous data are simulated from a Bayesian joint mixed-effects model fit to data from the Alzheimer's Disease Neuroimaging Initiative. Simulated progression events are algorithmically derived from the continuous assessments using a random forest model fit to the same data.ResultsWe find that power is approximately doubled with models of repeated continuous outcomes compared with the time-to-progression analysis. The simulations also demonstrate that a plausible informative missing data pattern can induce a bias that inflates treatment effects, yet 5% type I error is maintained.DiscussionGiven the relative inefficiency of time to progression, it should be avoided as a primary analysis approach in clinical trials of preclinical Alzheimer's disease

Neuroanatomical spread of amyloid β and tau in Alzheimer's disease: implications for primary prevention.

With recent advances in our understanding of the continuous pathophysiological changes that begin many years prior to symptom onset, it is now apparent that Alzheimer's disease cannot be adequately described by discrete clinical stages, but should also incorporate the continuum of biological changes that precede and underlie the clinical representation of the disease. By jointly considering longitudinal changes of all available biomarkers and clinical assessments, variation within individuals can be integrated into a single continuous measure of disease progression and used to identify the earliest pathophysiological changes. Disease time, a measure of disease severity, was estimated using a Bayesian latent time joint mixed-effects model applied to an array of imaging, biomarker and neuropsychological data. Trajectories of regional amyloid β and tau PET uptake were estimated as a function of disease time. Regions with early signs of elevated amyloid β uptake were used to form an early, focal composite and compared to a commonly used global composite, in a separate validation sample. Disease time was estimated in 279 participants (183 cognitively unimpaired individuals, 61 mild cognitive impairment and 35 Alzheimer's disease dementia patients) with available amyloid β and tau PET data. Amyloid β PET uptake levels in the posterior cingulate and precuneus start high and immediately increase with small increases of disease time. Early elevation in tau PET uptake was found in the inferior temporal lobe, amygdala, banks of the superior temporal sulcus, entorhinal cortex, middle temporal lobe, inferior parietal lobe and the fusiform gyrus. In a separate validation sample of 188 cognitively unimpaired individuals, the early, focal amyloid β PET composite showed a 120% increase in the accumulation rate of amyloid β compared to the global composite (P < 0.001), resulting in a 60% increase in the power to detect a treatment effect in a primary prevention trial design. Ordering participants on a continuous disease time scale facilitates the inspection of the earliest signs of amyloid β and tau pathology. To detect early changes in amyloid β pathology, focusing on the earliest sites of amyloid β accumulation results in more powerful and efficient study designs in early Alzheimer's disease. Targeted composites could be used to re-examine the thresholds for amyloid β-related study inclusion, especially as the field shifts to focus on primary and secondary prevention. Clinical trials of anti-amyloid β treatments may benefit from the use of focal composites when estimating drug effects on amyloid β and tau changes in populations with minimal amyloid β and tau pathology and limited expected short-term accumulation

Bayesian latent time joint mixed-effects model of progression in the Alzheimer's Disease Neuroimaging Initiative.

IntroductionWe characterize long-term disease dynamics from cognitively healthy to dementia using data from the Alzheimer's Disease Neuroimaging Initiative.MethodsWe apply a latent time joint mixed-effects model to 16 cognitive, functional, biomarker, and imaging outcomes in Alzheimer's Disease Neuroimaging Initiative. Markov chain Monte Carlo methods are used for estimation and inference.ResultsWe find good concordance between latent time and diagnosis. Change in amyloid positron emission tomography shows a moderate correlation with change in cerebrospinal fluid tau (ρ = 0.310) and phosphorylated tau (ρ = 0.294) and weaker correlation with amyloid-β 42 (ρ = 0.176). In comparison to amyloid positron emission tomography, change in volumetric magnetic resonance imaging summaries is more strongly correlated with cognitive measures (e.g., ρ = 0.731 for ventricles and Alzheimer's Disease Assessment Scale). The average disease trends are consistent with the amyloid cascade hypothesis.DiscussionThe latent time joint mixed-effects model can (1) uncover long-term disease trends; (2) estimate the sequence of pathological abnormalities; and (3) provide subject-specific prognostic estimates of the time until onset of symptoms

Predicting the course of Alzheimer's progression.

Alzheimer's disease is the most common neurodegenerative disease and is characterized by the accumulation of amyloid-beta peptides leading to the formation of plaques and tau protein tangles in brain. These neuropathological features precede cognitive impairment and Alzheimer's dementia by many years. To better understand and predict the course of disease from early-stage asymptomatic to late-stage dementia, it is critical to study the patterns of progression of multiple markers. In particular, we aim to predict the likely future course of progression for individuals given only a single observation of their markers. Improved individual-level prediction may lead to improved clinical care and clinical trials. We propose a two-stage approach to modeling and predicting measures of cognition, function, brain imaging, fluid biomarkers, and diagnosis of individuals using multiple domains simultaneously. In the first stage, joint (or multivariate) mixed-effects models are used to simultaneously model multiple markers over time. In the second stage, random forests are used to predict categorical diagnoses (cognitively normal, mild cognitive impairment, or dementia) from predictions of continuous markers based on the first-stage model. The combination of the two models allows one to leverage their key strengths in order to obtain improved accuracy. We characterize the predictive accuracy of this two-stage approach using data from the Alzheimer's Disease Neuroimaging Initiative. The two-stage approach using a single joint mixed-effects model for all continuous outcomes yields better diagnostic classification accuracy compared to using separate univariate mixed-effects models for each of the continuous outcomes. Overall prediction accuracy above 80% was achieved over a period of 2.5 years. The results further indicate that overall accuracy is improved when markers from multiple assessment domains, such as cognition, function, and brain imaging, are used in the prediction algorithm as compared to the use of markers from a single domain only

Superconductivity in the Correlated Pyrochlore Cd_2Re_2O_7

We report the observation of superconductivity in high-quality Cd$_2$Re$_2$O$_7$ single crystals with room-temperature pyrochlore structure. Resistivity and ac susceptibility measurements establish an onset transition temperature T$_c^{onset}$ = 1.47 K with transition width $\Delta$T$_c$ = 0.25 K. In applied magnetic field, the resistive transition shows a type-II character, with an approximately linear temperature-dependence of the upper critical field H$_{c2}$. The bulk nature of the superconductivity is confirmed by the specific heat jump with $\Delta$C = 37.9 mJ/mol-K. Using the $\gamma$ value extracted from normal-state specific heat data, we obtain $\Delta$C/$\gamma$T$_c$ = 1.29, close to the weak coupling BCS value. In the normal state, a negative Hall coefficient below 100 K suggests electron-like conduction in this material. The resistivity exhibits a quadratic T-dependence between 2 and 60 K, i.e., $\rho =\rho_0$+AT$^2$, indicative of Fermi-liquid behavior. The values of the Kadowaki-Woods ratio A/$\gamma^2$ and the Wilson ratio are comparable to that for strongly correlated materials.Comment: 4 pages, 5 figure

Temperature-dependent Raman spectroscopy in BaRuO3_3 systems

We investigated the temperature-dependence of the Raman spectra of a nine-layer BaRuO$_3$ single crystal and a four-layer BaRuO$_3$ epitaxial film, which show pseudogap formations in their metallic states. From the polarized and depolarized spectra, the observed phonon modes are assigned properly according to the predictions of group theory analysis. In both compounds, with decreasing temperature, while $A_{1g}$ modes show a strong hardening, $E_g$ (or $E_{2g}$) modes experience a softening or no significant shift. Their different temperature-dependent behaviors could be related to a direct Ru metal-bonding through the face-sharing of RuO$_6$. It is also observed that another $E_{2g}$ mode of the oxygen participating in the face-sharing becomes split at low temperatures in the four layer BaRuO$_3$. And, the temperature-dependence of the Raman continua between 250 $\sim$ 600 cm$^{-1}$ is strongly correlated to the square of the plasma frequency. Our observations imply that there should be a structural instability in the face-shared structure, which could be closely related to the pseudogap formation of BaRuO$_3$ systems.Comment: 8 pages, 6 figures. to be published in Phys. Rev.

Tight-binding study of high-pressure phase transitions in titanium: alpha to omega and beyond

We use a tight-binding total energy method, with parameters determined from a fit to first-principles calculations, to examine the newly discovered gamma phase of titanium. Our parameters were adjusted to accurately describe the alpha Ti-omega Ti phase transition, which is misplaced by density functional calculations. We find a transition from omega Ti to gamma Ti at 102 GPa, in good agreement with the experimental value of 116 GPa. Our results suggest that current density functional calculations will not reproduce the omega Ti-gamma Ti phase transition, but will instead predict a transition from omega Ti to the bcc beta Ti phase.Comment: 3 encapsulated Postscript figures, submitted to Phyical Review Letter

Effect of pressure on the Raman modes of antimony

The effect of pressure on the zone-center optical phonon modes of antimony in the A7 structure has been investigated by Raman spectroscopy. The A_g and E_g frequencies exhibit a pronounced softening with increasing pressure, the effect being related to a gradual suppression of the Peierls-like distortion of the A7 phase relative to a cubic primitive lattice. Also, both Raman modes broaden significantly under pressure. Spectra taken at low temperature indicate that the broadening is at least partly caused by phonon-phonon interactions. We also report results of ab initio frozen-phonon calculations of the A_g and E_g mode frequencies. Presence of strong anharmonicity is clearly apparent in calculated total energy versus atom displacement relations. Pronounced nonlinearities in the force versus displacement relations are observed. Structural instabilities of the Sb-A7 phase are briefly addressed in the Appendix.Comment: 10 pages, 8 figure

Power laws in a 2-leg ladder of interacting spinless fermions

We use the Density-Matrix Renormalization Group to study the single-particle and two-particle correlation functions of spinless fermions in the ground state of a quarter-filled ladder. This ladder consists of two chains having an in-chain extended Coulomb interaction reaching to third neighbor and coupled by inter-chain hopping. Within our short numerical coherence lengths, typically reaching ten to twenty sites, we find a strong renormalization of the interchain hopping and the existence of a dimensional crossover at smaller interactions. We also find power exponents for single-particle hopping and interchain polarization consistent with the single chain. The total charge correlation function has a larger power exponent and shows signs of a crossover from incoherent fermion hopping to coherent particle-hole pair motion between chains. There are no significant excitation energies.Comment: RevTex 4 file, 10 pages, 10 eps figure