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- Cavedo, E, et al.
(författare)
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The Road Ahead to Cure Alzheimer's Disease: Development of Biological Markers and Neuroimaging Methods for Prevention Trials Across all Stages and Target Populations
- 2014
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Ingår i: The journal of prevention of Alzheimer's disease. - : SERDI. - 2274-5807. ; 1:3, s. 181-202
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Tidskriftsartikel (refereegranskat)abstract
- Alzheimer's disease (AD) is a slowly progressing non-linear dynamic brain disease in which pathophysiological abnormalities, detectable in vivo by biological markers, precede overt clinical symptoms by many years to decades. Use of these biomarkers for the detection of early and preclinical AD has become of central importance following publication of two international expert working group's revised criteria for the diagnosis of AD dementia, mild cognitive impairment (MCI) due to AD, prodromal AD and preclinical AD. As a consequence of matured research evidence six AD biomarkers are sufficiently validated and partly qualified to be incorporated into operationalized clinical diagnostic criteria and use in primary and secondary prevention trials. These biomarkers fall into two molecular categories: biomarkers of amyloid-beta (Aβ) deposition and plaque formation as well as of tau-protein related hyperphosphorylation and neurodegeneration. Three of the six gold-standard ("core feasible) biomarkers are neuroimaging measures and three are cerebrospinal fluid (CSF) analytes. CSF Aβ 1-42 (Aβ1-42), also expressed as Aβ1-42 : Aβ1- 40 ratio, T-tau, and P-tau Thr181 & Thr231 proteins have proven diagnostic accuracy and risk enhancement in prodromal MCI and AD dementia. Conversely, having all three biomarkers in the normal range rules out AD. Intermediate conditions require further patient follow-up. Magnetic resonance imaging (MRI) at increasing field strength and resolution allows detecting the evolution of distinct types of structural and functional abnormality pattern throughout early to late AD stages. Anatomical or volumetric MRI is the most widely used technique and provides local and global measures of atrophy. The revised diagnostic criteria for “prodromal AD” and "mild cognitive impairment due to AD" include hippocampal atrophy (as the fourth validated biomarker), which is considered an indicator of regional neuronal injury. Advanced image analysis techniques generate automatic and reproducible measures both in regions of interest, such as the hippocampus and in an exploratory fashion, observer and hypothesis-indedendent, throughout the entire brain. Evolving modalities such as diffusion-tensor imaging (DTI) and advanced tractography as well as resting-state functional MRI provide useful additionally useful measures indicating the degree of fiber tract and neural network disintegration (structural, effective and functional connectivity) that may substantially contribute to early detection and the mapping of progression. These modalities require further standardization and validation. The use of molecular in vivo amyloid imaging agents (the fifth validated biomarker), such as the Pittsburgh Compound-B and markers of neurodegeneration, such as fluoro-2-deoxy-D-glucose (FDG) (as the sixth validated biomarker) support the detection of early AD pathological processes and associated neurodegeneration. How to use, interpret, and disclose biomarker results drives the need for optimized standardization. Multimodal AD biomarkers do not evolve in an identical manner but rather in a sequential but temporally overlapping fashion. Models of the temporal evolution of AD biomarkers can take the form of plots of biomarker severity (degree of abnormality) versus time. AD biomarkers can be combined to increase accuracy or risk. A list of genetic risk factors is increasingly included in secondary prevention trials to stratify and select individuals at genetic risk of AD. Although most of these biomarker candidates are not yet qualified and approved by regulatory authorities for their intended use in drug trials, they are nonetheless applied in ongoing clinical studies for the following functions: (i) inclusion/exclusion criteria, (ii) patient stratification, (iii) evaluation of treatment effect, (iv) drug target engagement, and (v) safety. Moreover, novel promising hypothesis-driven, as well as exploratory biochemical, genetic, electrophysiological, and neuroimaging markers for use in clinical trials are being developed. The current state-of-the-art and future perspectives on both biological and neuroimaging derived biomarker discovery and development as well as the intended application in prevention trials is outlined in the present publication.
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- Hill, M. S., et al.
(författare)
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Reconstruction of Family-Level Phylogenetic Relationships within Demospongiae (Porifera) Using Nuclear Encoded Housekeeping Genes
- 2013
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 8:1, s. e50437-
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Tidskriftsartikel (refereegranskat)abstract
- Background: Demosponges are challenging for phylogenetic systematics because of their plastic and relatively simple morphologies and many deep divergences between major clades. To improve understanding of the phylogenetic relationships within Demospongiae, we sequenced and analyzed seven nuclear housekeeping genes involved in a variety of cellular functions from a diverse group of sponges. Methodology/Principal Findings: We generated data from each of the four sponge classes (i.e., Calcarea, Demospongiae, Hexactinellida, and Homoscleromorpha), but focused on family-level relationships within demosponges. With data for 21 newly sampled families, our Maximum Likelihood and Bayesian-based approaches recovered previously phylogenetically defined taxa: Keratosap, Myxospongiaep, Spongillidap, Haploscleromorphap (the marine haplosclerids) and Democlaviap. We found conflicting results concerning the relationships of Keratosap and Myxospongiaep to the remaining demosponges, but our results strongly supported a clade of Haploscleromorphap+Spongillidap+Democlaviap. In contrast to hypotheses based on mitochondrial genome and ribosomal data, nuclear housekeeping gene data suggested that freshwater sponges (Spongillidap) are sister to Haploscleromorphap rather than part of Democlaviap. Within Keratosap, we found equivocal results as to the monophyly of Dictyoceratida. Within Myxospongiaep, Chondrosida and Verongida were monophyletic. A well-supported clade within Democlaviap, Tetractinellidap, composed of all sampled members of Astrophorina and Spirophorina (including the only lithistid in our analysis), was consistently revealed as the sister group to all other members of Democlaviap. Within Tetractinellidap, we did not recover monophyletic Astrophorina or Spirophorina. Our results also reaffirmed the monophyly of order Poecilosclerida (excluding Desmacellidae and Raspailiidae), and polyphyly of Hadromerida and Halichondrida. Conclusions/Significance: These results, using an independent nuclear gene set, confirmed many hypotheses based on ribosomal and/or mitochondrial genes, and they also identified clades with low statistical support or clades that conflicted with traditional morphological classification. Our results will serve as a basis for future exploration of these outstanding questions using more taxon- and gene-rich datasets.
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- Chung, Steve, et al.
(författare)
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Examining the clinical utility of lacosamide: pooled analyses of three phase II/III clinical trials.
- 2010
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Ingår i: CNS drugs. - : Springer Science and Business Media LLC. - 1172-7047. ; 24:12, s. 1041-54
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Tidskriftsartikel (refereegranskat)abstract
- Lacosamide is an antiepileptic drug (AED) approved for the adjunctive treatment of partial-onset seizures in adults. Completed phase II/III clinical trials of lacosamide provide a valuable opportunity to evaluate clinically relevant aspects of the resulting large patient pool.
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- Gutierrez-Esparza, A. J., et al.
(författare)
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Detection of nonlocal superpositions
- 2014
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Ingår i: Physical Review A. Atomic, Molecular, and Optical Physics. - 1050-2947 .- 1094-1622. ; 90:3, s. 032328-
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Tidskriftsartikel (refereegranskat)abstract
- We study in theory and experiment the verification of the Schmidt number of quantum correlated radiation fields. This measure of entanglement counts the number of global superpositions of product states which are needed to describe a compound quantum system. For unraveling a certain value of this measure, a family of entanglement and Schmidt number tests is constructed. The measurement of the whole class of witnesses is realized. By generating a path entangled two-photon state, we demonstrate the feasibility to directly count quantum superpositions.
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