Landmark Recognition in Alzheimer’s Dementia: Spared Implicit Memory for Objects Relevant for Navigation

Contains fulltext : 97074.pdf (publisher's version ) (Open Access)BACKGROUND: In spatial navigation, landmark recognition is crucial. Specifically, memory for objects placed at decision points on a route is relevant. Previous fMRI research in healthy adults showed higher medial-temporal lobe (MTL) activation for objects placed at decision points compared to non-decision points, even at an implicit level. Since there is evidence that implicit learning is intact in amnesic patients, the current study examined memory for objects relevant for navigation in patients with Alzheimer's dementia (AD). METHODOLOGY/PRINCIPAL FINDINGS: 21 AD patients participated with MTL atrophy assessed on MRI (mean MMSE = 21.2, SD = 4.0), as well as 20 age- and education-matched non-demented controls. All participants watched a 5-min video showing a route through a virtual museum with 20 objects placed at intersections (decision points) and 20 at simple turns (non-decision points). The instruction was to pay attention to the toys (half of the objects) for which they were supposedly tested later. Subsequently, a recognition test followed with the 40 previously presented objects among 40 distracter items (both toys and non-toys). Results showed a better performance for the non-toy objects placed at decision points than non-decision points, both for AD patients and controls. CONCLUSION/SIGNIFICANCE: Our findings indicate that AD patients with MTL damage have implicit memory for object information relevant for navigation. No decision point effect was found for the attended items. Possibly, focusing attention on the items occurred at the cost of the context information in AD, whereas the controls performed at an optimal level due to intact memory function.5 p

Impaired Representation of Geometric Relationships in Humans with Damage to the Hippocampal Formation

The pivotal role of the hippocampus for spatial memory is well-established. However, while neurophysiological and imaging studies suggest a specialization of the hippocampus for viewpoint-independent or allocentric memory, results from human lesion studies have been less conclusive. It is currently unclear whether disproportionate impairment in allocentric memory tasks reflects impairment of cognitive functions that are not sufficiently supported by regions outside the medial temporal lobe or whether the deficits observed in some studies are due to experimental factors. Here, we have investigated whether hippocampal contributions to spatial memory depend on the spatial references that are available in a certain behavioral context. Patients with medial temporal lobe lesions affecting systematically the right hippocampal formation performed a series of three oculomotor tasks that required memory of a spatial cue either in retinal coordinates or relative to a single environmental reference across a delay of 5000 ms. Stimulus displays varied the availability of spatial references and contained no complex visuo-spatial associations. Patients showed a selective impairment in a condition that critically depended on memory of the geometric relationship between spatial cue and environmental reference. We infer that regions of the medial temporal lobe, most likely the hippocampal formation, contribute to behavior in conditions that exceed the potential of viewpoint-dependent or egocentric representations. Apparently, this already applies to short-term memory of simple geometric relationships and does not necessarily depend on task difficulty or integration of landmarks into more complex representations. Deficient memory of basic geometric relationships may represent a core deficit that contributes to impaired performance in allocentric spatial memory tasks

Stress-Induced Reinstatement of Drug Seeking: 20 Years of Progress

In human addicts, drug relapse and craving are often provoked by stress. Since 1995, this clinical scenario has been studied using a rat model of stress-induced reinstatement of drug seeking. Here, we first discuss the generality of stress-induced reinstatement to different drugs of abuse, different stressors, and different behavioral procedures. We also discuss neuropharmacological mechanisms, and brain areas and circuits controlling stress-induced reinstatement of drug seeking. We conclude by discussing results from translational human laboratory studies and clinical trials that were inspired by results from rat studies on stress-induced reinstatement. Our main conclusions are (1) The phenomenon of stress-induced reinstatement, first shown with an intermittent footshock stressor in rats trained to self-administer heroin, generalizes to other abused drugs, including cocaine, methamphetamine, nicotine, and alcohol, and is also observed in the conditioned place preference model in rats and mice. This phenomenon, however, is stressor specific and not all stressors induce reinstatement of drug seeking. (2) Neuropharmacological studies indicate the involvement of corticotropin-releasing factor (CRF), noradrenaline, dopamine, glutamate, kappa/dynorphin, and several other peptide and neurotransmitter systems in stress-induced reinstatement. Neuropharmacology and circuitry studies indicate the involvement of CRF and noradrenaline transmission in bed nucleus of stria terminalis and central amygdala, and dopamine, CRF, kappa/dynorphin, and glutamate transmission in other components of the mesocorticolimbic dopamine system (ventral tegmental area, medial prefrontal cortex, orbitofrontal cortex, and nucleus accumbens). (3) Translational human laboratory studies and a recent clinical trial study show the efficacy of alpha-2 adrenoceptor agonists in decreasing stress-induced drug craving and stress-induced initial heroin lapse

Direct Whole-Genome Sequencing of Sputum Accurately Identifies Drug-Resistant Mycobacterium tuberculosis Faster than MGIT Culture Sequencing

This work was funded by the UCLH/UCL NIHR Biomedical Resource Centre (grant number BRC/176/III/JB/101350) and the PATHSEEK European Union's Seventh Programme for research, technological development and demonstration (grant number 304875)

Rapid Whole-Genome Sequencing of Mycobacterium tuberculosis Isolates Directly from Clinical Samples.

The rapid identification of antimicrobial resistance is essential for effective treatment of highly resistant Mycobacterium tuberculosis. Whole-genome sequencing provides comprehensive data on resistance mutations and strain typing for monitoring transmission, but unlike for conventional molecular tests, this has previously been achievable only from cultures of M. tuberculosis. Here we describe a method utilizing biotinylated RNA baits designed specifically for M. tuberculosis DNA to capture full M. tuberculosis genomes directly from infected sputum samples, allowing whole-genome sequencing without the requirement of culture. This was carried out on 24 smear-positive sputum samples, collected from the United Kingdom and Lithuania where a matched culture sample was available, and 2 samples that had failed to grow in culture. M. tuberculosis sequencing data were obtained directly from all 24 smear-positive culture-positive sputa, of which 20 were of high quality (>20× depth and >90% of the genome covered). Results were compared with those of conventional molecular and culture-based methods, and high levels of concordance between phenotypical resistance and predicted resistance based on genotype were observed. High-quality sequence data were obtained from one smear-positive culture-negative case. This study demonstrated for the first time the successful and accurate sequencing of M. tuberculosis genomes directly from uncultured sputa. Identification of known resistance mutations within a week of sample receipt offers the prospect for personalized rather than empirical treatment of drug-resistant tuberculosis, including the use of antimicrobial-sparing regimens, leading to improved outcomes

From Rapid Place Learning to Behavioral Performance: A Key Role for the Intermediate Hippocampus

Rapid place encoding by hippocampal neurons, as reflected by place-related firing, has been intensely studied, whereas the substrates that translate hippocampal place codes into behavior have received little attention. A key point relevant to this translation is that hippocampal organization is characterized by functional-anatomical gradients along the septotemporal axis: Whereas the ability of hippocampal neurons to encode accurate place information declines from the septal to temporal end, hippocampal connectivity to prefrontal and subcortical sites that might relate such place information to behavioral-control processes shows an opposite gradient. We examined in rats the impact of selective lesions to relevant parts of the hippocampus on behavioral tests requiring place learning (watermaze procedures) and on in vivo electrophysiological models of hippocampal encoding (long-term potentiation [LTP], place cells). We found that the intermediate hippocampus is necessary and largely sufficient for behavioral performance based on rapid place learning. In contrast, a residual septal pole of the hippocampus, although displaying intact electrophysiological indices of rapid information encoding (LTP, precise place-related firing, and rapid remapping), failed to sustain watermaze performance based on rapid place learning. These data highlight the important distinction between hippocampal encoding and the behavioral performance based on such encoding, and suggest that the intermediate hippocampus, where substrates of rapid accurate place encoding converge with links to behavioral control, is critical to translate rapid (one-trial) place learning into navigational performance

Classic and recent advances in understanding amnesia

Neurological amnesia has been and remains the focus of intense study, motivated by the drive to understand typical and atypical memory function and the underlying brain basis that is involved. There is now a consensus that amnesia associated with hippocampal (and, in many cases, broader medial temporal lobe) damage results in deficits in episodic memory, delayed recall, and recollective experience. However, debate continues regarding the patterns of preservation and impairment across a range of abilities, including semantic memory and learning, delayed recognition, working memory, and imagination. This brief review highlights some of the influential and recent advances in these debates and what they may tell us about the amnesic condition and hippocampal function

The Genome of a Pathogenic Rhodococcus: Cooptive Virulence Underpinned by Key Gene Acquisitions

We report the genome of the facultative intracellular parasite Rhodococcus equi, the only animal pathogen within the biotechnologically important actinobacterial genus Rhodococcus. The 5.0-Mb R. equi 103S genome is significantly smaller than those of environmental rhodococci. This is due to genome expansion in nonpathogenic species, via a linear gain of paralogous genes and an accelerated genetic flux, rather than reductive evolution in R. equi. The 103S genome lacks the extensive catabolic and secondary metabolic complement of environmental rhodococci, and it displays unique adaptations for host colonization and competition in the short-chain fatty acid–rich intestine and manure of herbivores—two main R. equi reservoirs. Except for a few horizontally acquired (HGT) pathogenicity loci, including a cytoadhesive pilus determinant (rpl) and the virulence plasmid vap pathogenicity island (PAI) required for intramacrophage survival, most of the potential virulence-associated genes identified in R. equi are conserved in environmental rhodococci or have homologs in nonpathogenic Actinobacteria. This suggests a mechanism of virulence evolution based on the cooption of existing core actinobacterial traits, triggered by key host niche–adaptive HGT events. We tested this hypothesis by investigating R. equi virulence plasmid-chromosome crosstalk, by global transcription profiling and expression network analysis. Two chromosomal genes conserved in environmental rhodococci, encoding putative chorismate mutase and anthranilate synthase enzymes involved in aromatic amino acid biosynthesis, were strongly coregulated with vap PAI virulence genes and required for optimal proliferation in macrophages. The regulatory integration of chromosomal metabolic genes under the control of the HGT–acquired plasmid PAI is thus an important element in the cooptive virulence of R. equi