Performance on a pattern separation task by Alzheimer's patients shows possible links between disrupted dentate gyrus activity and apolipoprotein E ∈4 status and cerebrospinal fluid amyloid-β42 levels

This is the final version of the article. Available from the publisher via the DOI in this record.INTRODUCTION: Emerging evidence suggests that decreased adult hippocampal neurogenesis represents an early critical event in the course of Alzheimer's disease (AD). In mice, adult neurogenesis is reduced by knock-in alleles for human apolipoprotein E (ApoE) ∈4. Decreased dentate gyrus (DG) neural progenitor cells proliferation has been observed in the triple-transgenic mouse model of AD (3xTg-AD); this reduction being directly associated with the presence of amyloid-β (Aβ) plaques and an increase in the number of Aβ-containing neurons in the hippocampus. Cognitive tasks involving difficult pattern separations have been shown to reflect DG activity and thus potentially neurogenesis in both animals and man. This study involved the administration of a pattern separation paradigm to Alzheimer's patients to investigate relationships between task performance and both ApoE status and cerebrospinal fluid (CSF) Aβ42 levels. METHODS: The CDR System pattern separation task involves the presentation of pictures that must later be discriminated from closely similar pictures. This paper presents pattern separation data from 66 mild to moderate AD patients, of which 50 were genotyped and 65 in whom CSF Aβ42 was measured. RESULTS: ApoE ∈4 homozygotes were not compromised on the easy pattern separations compared with the other patients, but they were statistically significantly poorer at the difficult separations. In all patients CSF Aβ42 correlated significantly with the ability to make the difficult discriminations, but not easier discriminations. Pattern separation speed correlated negatively with CSF Aβ42, and thus the association was not due to increased impulsivity. CONCLUSIONS: These are, to our knowledge, the first human pattern separation data to suggest a possible genetic link to poor hippocampal neurogenesis in AD, as well as a relationship to Aβ42. Therapies which target neurogenesis may thus be useful in preventing the early stages of AD, notably in ApoE ∈4 homocygotes.This study was financially supported by AstraZeneca, Sweden

Dynamical symmetry breaking as the origin of the zero-dcdc-resistance state in an acac-driven system

Under a strong $ac$ drive the zero-frequency linear response dissipative resistivity $\rho_{d}(j=0)$ of a homogeneous state is allowed to become negative. We show that such a state is absolutely unstable. The only time-independent state of a system with a $\rho_{d}(j=0)<0$ is characterized by a current which almost everywhere has a magnitude $j_{0}$ fixed by the condition that the nonlinear dissipative resistivity $\rho_{d}(j_{0}^{2})=0$. As a result, the dissipative component of the $dc$ electric field vanishes. The total current may be varied by rearranging the current pattern appropriately with the dissipative component of the $dc$-electric field remaining zero. This result, together with the calculation of Durst \emph{et. al.}, indicating the existence of regimes of applied $ac$ microwave field and $dc$ magnetic field where $\rho_{d}(j=0)<0$, explains the zero-resistance state observed by Mani \emph{et. al.} and Zudov \emph{et. al.}.Comment: Published versio

Sn Vacancies in Photorefractive Sn\u3csub\u3e2\u3c/sub\u3eP\u3csub\u3e2\u3c/sub\u3eS\u3csub\u3e6\u3c/sub\u3e Crystals: An Electron Paramagnetic Resonance Study of an Optically Active Hole Trap

Electron paramagnetic resonance (EPR) is used to identify the singly ionized charge state of the Sn vacancy (V−Sn) in single crystals of Sn2P2S6 (often referred to as SPS). These vacancies, acting as a hole trap, are expected to be important participants in the photorefractive effect observed in undoped SPS crystals. In as-grown crystals, the Sn vacancies are doubly ionized (V2−Sn) with no unpaired spins. They are then converted to a stable EPR-active state when an electron is removed (i.e., a hole is trapped) during an illumination below 100 K with 633 nm laser light. The resulting EPR spectrum has g-matrix principal values of 2.0079, 2.0231, and 1.9717. There are resolved hyperfine interactions with two P neighbors and one Sn neighbor. The isotropic portions of these hyperfine matrices are 167 and 79 MHz for the two 31P neighbors and 8504 MHz for the one Sn neighbor (this latter value is the average for 117Sn and 119Sn). These V−Sn vacancies are shallow acceptors with the hole occupying a diffuse wave function that overlaps the neighboring Sn2+ ion and (P2S6)4− anionic unit. Using a general-order kinetics approach, an analysis of isothermal decay curves of the V−Sn EPR spectrum in the 107–115 K region gives an activation energy of 283 meV

Sulfur Vacancies in Photorefractive Sn\u3csub\u3e2\u3c/sub\u3eP\u3csub\u3e2\u3c/sub\u3eS\u3csub\u3e6\u3c/sub\u3e Crystals

A photoinduced electron paramagnetic resonance (EPR) spectrum in single crystals of Sn2P2S6 (SPS) is assigned to an electron trapped at a sulfur vacancy. These vacancies are unintentionally present in undoped SPS crystals and are expected to play an important role in the photorefractive behavior of the material. Nonparamagnetic sulfur vacancies are formed during the initial growth of the crystal. Subsequent illumination below 100 K with 442 nm laser light easily converts these vacancies to EPR-active defects. The resulting S = 1/2 spectrum shows well-resolved and nearly isotropic hyperfine interactions with two P ions and two Sn ions. Partially resolved interactions with four additional neighboring Sn ions are also observed. Principal values of the g matrix are 1.9700, 1.8946, and 1.9006, with the corresponding principal axes along the a, b, and c directions in the crystal. The isotropic parts of the two primary 31P hyperfine interactions are 19.5 and 32.6 MHz and the isotropic parts of the two primary Sn hyperfine interactions are 860 and 1320 MHz (the latter values are each an average for 117Sn and 119Sn). These hyperfine results suggest that singly ionized sulfur vacancies have a diffuse wave function in SPS crystals, and thus are shallow donors. Before illumination, sulfur vacancies are in the doubly ionized charge state because of compensation by unidentified acceptors. They then trap an electron during illumination. The EPR spectrum from the sulfur vacancy is destroyed when a crystal is heated above 120 K in the dark and reappears when the crystal is illuminated again at low temperature

Structural Origin of Recovered Ferroelectricity in BaTiO3_3 Nanoparticles

Nanoscale BaTiO$_3$ particles (~10 nm) prepared by ball-milling a mixture of oleic acid and heptane have been reported to have an electric polarization several times larger than that for bulk BaTiO$_3$. In this work, detailed local, intermediate, and long-range structural studies are combined with spectroscopic measurements to develop a model structure of these materials. The X-ray spectroscopic measurements reveal large Ti off-centering as the key factor producing the large spontaneous polarization in the nanoparticles. Temperature-dependent lattice parameter changes reveal the sharpening of the structural phase transitions in these BaTiO$_3$ nanoparticles compared to the pure nanoparticle systems. Sharp crystalline-type peaks in the barium oleate Raman spectra suggest that this component in the composite core-shell matrix, a product of mechanochemical synthesis, stabilizes an enhanced polar structural phase of the BaTiO$_3$ core nanoparticles.Comment: 5 figures in main text. 1 table and 3 figures in supplementary documen

Harvesting Single Ferroelectric Domain Stressed Nanoparticles for Optical and Ferroic Applications

We describe techniques to selectively harvest single ferroelectric domain nanoparticles of BaTiO3 as small as 9 nm from a plethora of nanoparticles produced by mechanical grinding. High resolution transmission electron microscopy imaging shows the unidomain atomic structure of the nanoparticles and reveals compressive and tensile surface strains which are attributed to the preservation of ferroelectric behavior in these particles. We demonstrate the positive benefits of using harvested nanoparticles in disparate liquid crystal systems

Dose ratio proton radiography using the proximal side of the Bragg peak

Purpose: In recent years there has been a movement towards single-detector proton radiography, due to its potential ease of implementation within the clinical environment. One such single-detector technique is the dose ratio method, in which the dose maps from two pristine Bragg peaks are recorded beyond the patient. To date, this has only been investigated on the distal side of the lower energy Bragg peak, due to the sharp fall-off. We investigate the limits and applicability of the dose ratio method on the proximal side of the lower energy Bragg peak, which has the potential to allow a much wider range of water-equivalent thicknesses (WET) to be imaged. Comparisons are made with the use of the distal side of the Bragg peak. Methods: Using the analytical approximation for the Bragg peak we generated theoretical dose ratio curves for a range of energy pairs, and then determined how an uncertainty in the dose ratio would translate to a spread in the WET estimate. By defining this spread as the accuracy one could achieve in the WET estimate, we were able to generate look-up graphs of the range on the proximal side of the Bragg peak that one could reliably use. These were dependent on the energy pair, noise level in the dose ratio image and the required accuracy in the WET. Using these look-up graphs we investigated the applicability of the technique for a range of patient treatment sites. We validated the theoretical approach with experimental measurements using a complementary metal oxide semiconductor active pixel sensor (CMOS APS), by imaging a small sapphire sphere in a high energy proton beam. Results: Provided the noise level in the dose ratio image was 1% or less, a larger spread of WETs could be imaged using the proximal side of the Bragg peak (max 5.31 cm) compared to the distal side (max 2.42 cm). In simulation it was found that, for a pediatric brain, it is possible to use the technique to image a region with a square field equivalent size of 7.6 cm2, for a required accuracy in the WET of 3 mm and a 1% noise level in the dose ratio image. The technique showed limited applicability for other patient sites. The CMOS APS demonstrated a good accuracy, with a root-mean-square-error of 1.6 mm WET. The noise in the measured images was found to be σ =1.2% (standard deviation) and theoretical predictions with a 1.96σ noise level showed good agreement with the measured errors. Conclusions: After validating the theoretical approach with measurements, we have shown that the use of the proximal side of the Bragg peak when performing dose ratio imaging is feasible, and allows for a wider dynamic range than when using the distal side. The dynamic range available increases as the demand on the accuracy of the WET decreases. The technique can only be applied to clinical sites with small maximum WETs such as for pediatric brains

Achieving enhanced gain in photorefractive polymers by eliminating electron contributions using large bias fields

Photorefractive polymers have been extensively studied for over two decades and have found applications in holographic displays and optical image processing. The complexity of these materials arises from multiple charge contributions, for example, leading to the formation of competing photorefractive gratings. It has been recently shown that in a photorefractive polymer at relatively moderate applied electric fields the primary charge carriers (holes) establish an initial grating, followed by a subsequent competing grating (electrons) resulting in a decreased two-beam coupling and diffraction efficiencies. In this paper, it is shown that with relatively large sustainable bias fields, the two-beam coupling efficiency is enhanced owing to a decreased electron contribution. These results also explain the cause of dielectric breakdown experienced under large bias fields. Our conclusions are supported by self-pumped transient two-beam coupling and photocurrent measurements as a function of applied bias fields at different wavelengths

Characterization of monomeric and soluble aggregated Aβ in Down's syndrome and Alzheimer's disease brains

The major characteristics of Alzheimer's disease (AD) are amyloid plaques, consisting of aggregated beta amyloid (Aβ) peptides, together with tau pathology (tangles, neuropil treads and dystrophic neurites surrounding the plaques), in the brain. Down's syndrome (DS) individuals are at increased risk to develop AD-type pathology; most DS individuals have developed substantial pathology already at the age of 40. DS individuals have an extra copy of chromosome 21, harbouring the amyloid precursor protein gene (APP). Our aim was to investigate the Aβ peptide pattern in DS and AD brains to investigate differences in their amyloid deposition and aggregation, respectively. Cortical tissue from patients with DS (with amyloid pathology), sporadic AD and controls were homogenized and fractionated into TBS (water soluble) and formic acid (water insoluble) fractions. Immunoprecipitation (IP) was performed using a variety of antibodies targeting different Aβ species including oligomeric Aβ. Mass spectrometry was then used to evaluate the presence of Aβ species in the different patient groups. A large number of Aβ peptides were identified including Aβ1-X, 2-X, 3-X, 4-X, 5-X, 11-X, and Aβ peptides extended N terminally of the BACE1 cleavage site and ending at amino 15 in the Aβ sequence APP/Aβ(-X to 15), as well as peptides post-translationally modified by pyroglutamate formation. Most Aβ peptides had higher abundance in AD and DS compared to controls, except the APP/Aβ(-X to 15) peptides which were most abundant in DS followed by controls and AD. Furthermore, the abundancies of AβX-40 and AβX-34 were increased in DS compared with AD. Aβ1-40, Aβ1-42, and Aβ4-42 were identified as the main constitutes of protofibrils (IP'd using mAb158) and higher relative Aβ1-42 signals were obtained compared with samples IP'd with 6E10 + 4G8, indicating that the protofibrils/oligomers were enriched with peptides ending at amino acid 42. All Aβ peptides found in AD were also present in DS indicating similar pathways of Aβ peptide production, degradation and accumulation, except for APP/Aβ(-X to 15). Likewise, the Aβ peptides forming protofibrils/oligomers in both AD and DS were similar, implying the possibility that treatment with clinical benefit in sporadic AD might also be beneficial for subjects with DS