Microstructural Alterations in Hippocampal Subfields Mediate Age-Related Memory Decline in Humans.

Aging, even in the absence of clear pathology of dementia, is associated with cognitive decline. Neuroimaging, especially diffusion-weighted imaging, has been highly valuable in understanding some of these changes in live humans, non-invasively. Traditional tensor techniques have revealed that the integrity of the fornix and other white matter tracts significantly deteriorates with age, and that this deterioration is highly correlated with worsening cognitive performance. However, traditional tensor techniques are still not specific enough to indict explicit microstructural features that may be responsible for age-related cognitive decline and cannot be used to effectively study gray matter properties. Here, we sought to determine whether recent advances in diffusion-weighted imaging, including Neurite Orientation Dispersion and Density Imaging (NODDI) and Constrained Spherical Deconvolution, would provide more sensitive measures of age-related changes in the microstructure of the medial temporal lobe. We evaluated these measures in a group of young (ages 20-38 years old) and older (ages 59-84 years old) adults and assessed their relationships with performance on tests of cognition. We found that the fiber density (FD) of the fornix and the neurite density index (NDI) of the fornix, hippocampal subfields (DG/CA3, CA1, and subiculum), and parahippocampal cortex, varied as a function of age in a cross-sectional cohort. Moreover, in the fornix, DG/CA3, and CA1, these changes correlated with memory performance on the Rey Auditory Verbal Learning Test (RAVLT), even after regressing out the effect of age, suggesting that they were capturing neurobiological properties directly related to performance in this task. These measures provide more details regarding age-related neurobiological properties. For example, a change in fiber density could mean a reduction in axonal packing density or myelination, and the increase in NDI observed might be explained by changes in dendritic complexity or even sprouting. These results provide a far more comprehensive view than previously determined on the possible system-wide processes that may be occurring because of healthy aging and demonstrate that advanced diffusion-weighted imaging is evolving into a powerful tool to study more than just white matter properties

Recognition Memory Dysfunction Relates to Hippocampal Subfield Volume: A Study of Cognitively Normal and Mildly Impaired Older Adults.

ObjectivesThe current study examined recognition memory dysfunction and its neuroanatomical substrates in cognitively normal older adults and those diagnosed with mild cognitive impairment (MCI).MethodsParticipants completed the Mnemonic Similarity Task, which provides simultaneous measures of recognition memory and mnemonic discrimination. They also underwent structural neuroimaging to assess volume of medial temporal cortex and hippocampal subfields.ResultsAs expected, individuals diagnosed with MCI had significantly worse recognition memory performance and reduced volume across medial temporal cortex and hippocampal subfields relative to cognitively normal older adults. After controlling for diagnostic group differences, however, recognition memory was significantly related to whole hippocampus volume, and to volume of the dentate gyrus/CA3 subfield in particular. Recognition memory was also related to mnemonic discrimination, a fundamental component of episodic memory that has previously been linked to dentate gyrus/CA3 structure and function.DiscussionResults reveal that hippocampal subfield volume is sensitive to individual differences in recognition memory in older adults independent of clinical diagnosis. This supports the notion that episodic memory declines along a continuum within this age group, not just between diagnostic groups

Tetravalent Colloids by Nematic Wetting

In an elegant paper, D. Nelson suggested a method to produce tetravalent colloids based on a tetrahedral configuration created on the surface of a spherical particle. It emerges from a two-dimensional nematic liquid crystal placed on a sphere due to the presence of four 1/2 disclinations, i.e., topological defects in the orientational order. In this paper we show that such a tetrahedral configuration also occurs in the wetting layers which form around spheres dispersed in a liquid crystal above the nematic-isotropic phase transition. Nematic wetting therefore offers an alternative route towards tetravalent colloids.Comment: 7 pages, 4 figures, submitted to Europhys. Let

New Uses for Sensitivity Analysis: How Different Movement Tasks Effect Limb Model Parameter Sensitivity

Original results for a newly developed eight-order nonlinear limb antagonistic muscle model of elbow flexion and extension are presented. A wider variety of sensitivity analysis techniques are used and a systematic protocol is established that shows how the different methods can be used efficiently to complement one another for maximum insight into model sensitivity. It is explicitly shown how the sensitivity of output behaviors to model parameters is a function of the controller input sequence, i.e., of the movement task. When the task is changed (for instance, from an input sequence that results in the usual fast movement task to a slower movement that may also involve external loading, etc.) the set of parameters with high sensitivity will in general also change. Such task-specific use of sensitivity analysis techniques identifies the set of parameters most important for a given task, and even suggests task-specific model reduction possibilities

Neural substrates of mnemonic discrimination: A whole-brain fMRI investigation.

IntroductionA fundamental component of episodic memory is the ability to differentiate new and highly similar events from previously encountered events. Numerous functional magnetic resonance imaging (fMRI) studies have identified hippocampal involvement in this type of mnemonic discrimination (MD), but few studies have assessed MD-related activity in regions beyond the hippocampus. Therefore, the current fMRI study examined whole-brain activity in healthy young adults during successful discrimination of the test phase of the Mnemonic Similarity Task.MethodIn the study phase, participants made "indoor"/"outdoor" judgments to a series of objects. In the test phase, they made "old"/"new" judgments to a series of probe objects that were either repetitions from the memory set (targets), similar to objects in the memory set (lures), or novel. We assessed hippocampal and whole-brain activity consistent with MD using a step function to identify where activity to targets differed from activity to lures with varying degrees of similarity to targets (high, low), responding to them as if they were novel.ResultsResults revealed that the hippocampus and occipital cortex exhibited differential activity to repeated stimuli relative to even highly similar stimuli, but only hippocampal activity predicted discrimination performance.ConclusionsThese findings are consistent with the notion that successful MD is supported by the hippocampus, with auxiliary processes supported by cortex (e.g., perceptual discrimination)

Gated rotation mechanism of site-specific recombination by ϕC31 integrase

Integrases, such as that of the Streptomyces temperate bacteriophage ϕC31, promote site-specific recombination between DNA sequences in the bacteriophage and bacterial genomes to integrate or excise the phage DNA. ϕC31 integrase belongs to the serine recombinase family, a large group of structurally related enzymes with diverse biological functions. It has been proposed that serine integrases use a “subunit rotation” mechanism to exchange DNA strands after double-strand DNA cleavage at the two recombining att sites, and that many rounds of subunit rotation can occur before the strands are religated. We have analyzed the mechanism of ϕC31 integrase-mediated recombination in a topologically constrained experimental system using hybrid “phes” recombination sites, each of which comprises a ϕC31 att site positioned adjacent to a regulatory sequence recognized by Tn3 resolvase. The topologies of reaction products from circular substrates containing two phes sites support a right-handed subunit rotation mechanism for catalysis of both integrative and excisive recombination. Strand exchange usually terminates after a single round of 180° rotation. However, multiple processive “360° rotation” rounds of strand exchange can be observed, if the recombining sites have nonidentical base pairs at their centers. We propose that a regulatory “gating” mechanism normally blocks multiple rounds of strand exchange and triggers product release after a single round

Model simulation studies to clarify the effect on saccadic eye movements of initial condition velocities set by the Vestibular Ocular Reflex (VOR)

Voluntary active head rotations produced vestibulo-ocular reflex eye movements (VOR) with the subject viewing a fixation target. When this target jumped, the size of the refixation saccades were a function of the ongoing initial velocity of the eye. Saccades made against the VOR were larger in magnitude. Simulation of a reciprocally innervated model eye movement provided results comparable to the experimental data. Most of the experimental effect appeared to be due to linear summation for saccades of 5 and 10 degree magnitude. For small saccades of 2.5 degrees, peripheral nonlinear interaction of state variables in the neuromuscular plant also played a role as proven by comparable behavior in the simulated model with known controller signals

Estimating Time-Varying Effects of Prognostic Factors for Stomach Cancer Patients within a Dynamic Grouped Cox Model

We describe the identification of prognostic factors in the framework of a completely resected stomach cancer survival-study. For the analysis the dynamic grouped Cox-Model was used allowing for time-varying covariate effects. Therefore the hazard rate might be non-proportional. As estimation concept we applied the posterior mode, computed by iteratively weighted Kalman filtering and smoothing steps. The medical study and questions are described, the statistical method is illustrated, the results are given and interpreted and the method is discussed