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

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

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

Effects of Peroral Omega-3 Fatty Acid Supplementation on Cerebrospinal Fluid Biomarkers in Patients with Alzheimer’s Disease: A Randomized Controlled Trial—The OmegAD Study

Background: Studies have suggested a connection between a decrease in the levels of polyunsaturated fatty acids (PUFAs) and Alzheimer’s disease (AD). We aimed to assess the effect of supplementation with omega-3 fatty acids (n-3 FAs) on biomarkers analyzed in the cerebrospinal fluid (CSF) of patients diagnosed with AD. / Objective: To investigate the effects of daily supplementation with 2.3 g of PUFAs in AD patients on the biomarkers in CSF described below. We also explored the possible correlation between these biomarkers and the performance in the cognitive test Mini-Mental State Examination (MMSE). / Methods: Thirty-three patients diagnosed with AD were randomized to either treatment with a daily intake of 2.3 g of n-3 FAs (n  =  18) or placebo (n  =  15). CSF samples were collected at baseline and after six months of treatment, and the following biomarkers were analyzed: Aβ 38, Aβ 40, Aβ 42, t-tau, p-tau, neurofilament light (NfL), chitinase-3-like protein 1 (YKL-40), acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), soluble IL-1 receptor type II (sIL-1RII), and IL-6. / Results: There were no significant differences between the groups concerning the level of the different biomarkers in the CSF at baseline. Within the treatment group, there was a small but significant increase in both YKL-40 (p = 0.04) and NfL (p = 0.03), while the other CSF biomarkers remained stable. / Conclusion: Supplementation with n-3 FAs had a statistically significant effect on NfL and YKL-40, resulting in an increase of both biomarkers, indicating a possible increase of inflammatory response and axonal damage. This increase in biomarkers did not correlate with MMSE score. / Trial registration: clinicaltrial.gov Identifier: NCT00211159

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

Time Dynamics of Self-Pumped Reflection Gratings in a Photorefractive Polymer

The time dynamics of self-pumped reflection gratings in a commonly used photorefractive polymer PDCST:PVK:ECZ-BBP:C60 with no additional electron sources or traps is investigated. While holes are normally the mobile charges and responsible for grating formation, our experimental observations, analyzed using multi-exponential fitting curves, show evidence of electrons in addition to holes as charge carriers, particularly above an applied field of 40 V/μm. The dependence of effective carrier mobilities on the applied electric field, deduced from experimental results, show stronger field dependence of electron mobility at high electric fields. At an applied field of 70 V/μm, electron and hole mobilities become approximately equal, and the contribution of electrons on grating formation becomes significant

Magnetotransport in two-dimensional electron gas at large filling factors

We derive the quantum Boltzmann equation for the two-dimensional electron gas in a magnetic field such that the filling factor $\nu \gg 1$. This equation describes all of the effects of the external fields on the impurity collision integral including Shubnikov-de Haas oscillations, smooth part of the magnetoresistance, and non-linear transport. Furthemore, we obtain quantitative results for the effect of the external microwave radiation on the linear and non-linear $dc$ transport in the system. Our findings are relevant for the description of the oscillating resistivity discovered by Zudov {\em et al.}, zero-resistance state discovered by Mani {\em et al.} and Zudov {\em et al.}, and for the microscopic justification of the model of Andreev {\em et al.}. We also present semiclassical picture for the qualitative consideration of the effects of the applied field on the collision integral.Comment: 28 pages, 19 figures; The discussion of the role of the effect of the microwave field on the distribution function is revised (see also cond-mat/0310668). Accepted in Phys. Rev.

Nonequilibrium phenomena in high Landau levels

Developments in the physics of 2D electron systems during the last decade have revealed a new class of nonequilibrium phenomena in the presence of a moderately strong magnetic field. The hallmark of these phenomena is magnetoresistance oscillations generated by the external forces that drive the electron system out of equilibrium. The rich set of dramatic phenomena of this kind, discovered in high mobility semiconductor nanostructures, includes, in particular, microwave radiation-induced resistance oscillations and zero-resistance states, as well as Hall field-induced resistance oscillations and associated zero-differential resistance states. We review the experimental manifestations of these phenomena and the unified theoretical framework for describing them in terms of a quantum kinetic equation. The survey contains also a thorough discussion of the magnetotransport properties of 2D electrons in the linear response regime, as well as an outlook on future directions, including related nonequilibrium phenomena in other 2D electron systems.Comment: 60 pages, 41 figure