White Matter Hyperintensities and Cognition: Testing the Reserve Hypothesis

OBJECTIVE: White matter hyperintensities (WMH), visualized on T2-weighted MRI, are thought to reflect small-vessel vascular disease. Much like other markers of brain disease, the association between WMH and cognition is imperfect. The concept of reserve may account for this imperfect relationship. The purpose of this study was to test the reserve hypothesis in the association between WMH severity and cognition. We hypothesized that individuals with higher amounts of reserve would be able to tolerate greater amounts of pathology than those with lower reserve. METHODS: Neurologically healthy older adults (n=717) from a community-based study received structural MRI, neuropsychological assessment, and evaluation of reserve. WMH volume was quantified algorithmically. We derived latent constructs representing four neuropsychological domains, a measure of cognitive reserve, and a measure of brain reserve. Measures of cognitive and brain reserve consisted of psychosocial (e.g., education) and anthropometric (e.g., craniometry) variables, respectively. RESULTS: Increased WMH volume was associated with poorer cognition and higher cognitive and brain reserve were associated with better cognition. Controlling for speed/executive function or for language function, those with higher estimates of cognitive reserve had significantly greater degrees of WMH volume, particularly among women. Controlling for cognitive functioning across all domains, individuals with higher estimates of brain reserve had significantly greater WMH volume. CONCLUSIONS: For any given level of cognitive function, those with higher reserve had more pathology in the form of WMH, suggesting that they are better able to cope with pathology than those with lower reserve. Both brain reserve and cognitive reserve appear to mitigate the impact of pathology on cognition

Brain tissue volume changes following weight gain in adults with anorexia nervosa

Objective: To measure brain volume deficits among underweight patients with anorexia nervosa (AN) compared to control participants and evaluate the reversibility of these deficits with short-term weight restoration. Method: Brain volume changes in gray matter (GM), white matter (WM), and cerebrospinal fluid (CSF) were examined in 32 adult women with AN and compared to 21, age and body mass index-range matched control women. Results: Patients with AN had a significant increase in GM (p = .006, η2 = 0.14) and WM volume (p = .001, η2 = 0.19) following weight restoration. Patients on average had lower levels of GM at low weight (647.63 ± 62.07 ml) compared to controls (679.93 ± 53.31 ml), which increased with weight restoration (662.64 ± 69.71 ml), but did not fully normalize. Discussion: This study suggests that underweight adult patients with AN have reduced GM and WM volumes that increase with short-term weight restoration

Complete Sequencing of pNDM-HK Encoding NDM-1 Carbapenemase from a Multidrug-Resistant Escherichia coli Strain Isolated in Hong Kong

BACKGROUND: The emergence of plasmid-mediated carbapenemases, such as NDM-1 in Enterobacteriaceae is a major public health issue. Since they mediate resistance to virtually all β-lactam antibiotics and there is often co-resistance to other antibiotic classes, the therapeutic options for infections caused by these organisms are very limited. METHODOLOGY: We characterized the first NDM-1 producing E. coli isolate recovered in Hong Kong. The plasmid encoding the metallo-β-lactamase gene was sequenced. PRINCIPAL FINDINGS: The plasmid, pNDM-HK readily transferred to E. coli J53 at high frequencies. It belongs to the broad host range IncL/M incompatibility group and is 88803 bp in size. Sequence alignment showed that pNDM-HK has a 55 kb backbone which shared 97% homology with pEL60 originating from the plant pathogen, Erwina amylovora in Lebanon and a 28.9 kb variable region. The plasmid backbone includes the mucAB genes mediating ultraviolet light resistance. The 28.9 kb region has a composite transposon-like structure which includes intact or truncated genes associated with resistance to β-lactams (bla(TEM-1), bla(NDM-1), Δbla(DHA-1)), aminoglycosides (aacC2, armA), sulphonamides (sul1) and macrolides (mel, mph2). It also harbors the following mobile elements: IS26, ISCR1, tnpU, tnpAcp2, tnpD, ΔtnpATn1 and insL. Certain blocks within the 28.9 kb variable region had homology with the corresponding sequences in the widely disseminated plasmids, pCTX-M3, pMUR050 and pKP048 originating from bacteria in Poland in 1996, in Spain in 2002 and in China in 2006, respectively. SIGNIFICANCE: The genetic support of NDM-1 gene suggests that it has evolved through complex pathways. The association with broad host range plasmid and multiple mobile genetic elements explain its observed horizontal mobility in multiple bacterial taxa

Robust estimation of bacterial cell count from optical density

Optical density (OD) is widely used to estimate the density of cells in liquid culture, but cannot be compared between instruments without a standardized calibration protocol and is challenging to relate to actual cell count. We address this with an interlaboratory study comparing three simple, low-cost, and highly accessible OD calibration protocols across 244 laboratories, applied to eight strains of constitutive GFP-expressing E. coli. Based on our results, we recommend calibrating OD to estimated cell count using serial dilution of silica microspheres, which produces highly precise calibration (95.5% of residuals <1.2-fold), is easily assessed for quality control, also assesses instrument effective linear range, and can be combined with fluorescence calibration to obtain units of Molecules of Equivalent Fluorescein (MEFL) per cell, allowing direct comparison and data fusion with flow cytometry measurements: in our study, fluorescence per cell measurements showed only a 1.07-fold mean difference between plate reader and flow cytometry data

Cognitive Correlates of Anterolateral Entorhinal Cortex Volume Differences in Older Adults

Alzheimer’s disease pathology first appears in the medial temporal lobe (MTL): in particular, in the anterolateral region of the entorhinal cortex (alERC). However, the scientific community has only recently begun to appreciate the importance of the subdivision of the human entorhinal cortex, and as such, our understanding of the alERC’s cognitive roles and how it fits into models of MTL function remains limited. In this dissertation, I describe a series of studies inspired by findings from the animal literature, which shed light on the cognitive functions supported by the alERC. Using structural volumetry, I quantified the volumes of the alERC and other MTL regions in a group of ostensibly healthy older adults with varying degrees of cognitive decline. I compared participants’ structural differences to their performance on behavioral tasks that we hypothesized represented cognitive functions supported by the alERC. Specifically, I investigated how alERC structural differences were related to performance on the Montreal Cognitive Assessment (MoCA), a standard neuropsychological assessment used in the diagnosis of AD (Chapter 2), as well as eyetracking-based behavioral tasks assessing intra-item configural processing (Chapter 3) and object-in-place memory (Chapter 4), cognitive functions which the rodent literature suggest are supported by the alERC. I found that participants who scored below the MoCA threshold score (indicating possible AD) had smaller alERC volumes (Chapter 2), demonstrating that alERC volume is related to cognitive decline. Further, intra-item configural processing – regardless of an object’s novelty – was strongly predicted by alERC volume, but not by the volume of any other MTL subregion (Chapter 3). Finally, alERC (and parahippocampal cortex) volume was also related to object-in-place memory for items in everyday scenes, but no such relationship was found for object-trace memory (Chapter 4). Together, these studies suggest that the alERC may support aspects of the spatial processing of objects, advancing our understanding of the cognitive correlates of the alERC. More pragmatically, the alERC-specific tasks I developed may prove useful in early screening for AD and evaluating its progression.Ph.D

Investigating the Mechanisms of Forgetting in Aging Using Eyetracking

Recent studies in rodents (McTighe et al, 2010; Burke et al, 2010) have suggested that forgetting is caused by the misidentification of novel stimuli as being familiar, matching the predictions of the representational-hierarchical model of Saksida & Bussey (2010). Here, we tested this idea in humans. Three groups of participants (young, healthy elders, elders at-risk for MCI) viewed novel and repeated stimuli in a continuous viewing task while their eye movements were recorded. According to the eye-movement based memory effect (Ryan et al, 2000) individuals make fewer fixations on items which are perceived as familiar. As interference increased, eye-movements directed to the novel stimuli declined, indicating these novel items were perceived as familiar. This effect was stronger in groups more vulnerable to interference (eg. at-risk elders). These results suggest that forgetting in humans, like rats, is driven by the misidentification of novel items as being familiar.MAS

Recognition Memory Impairments Caused by False Recognition of Novel Objects

A fundamental assumption underlying most current theories of amnesia is that memory impairments arise because previously studied information either is lost rapidly or is made inaccessible (i.e., the old information appears to be new). Recent studies in rodents have challenged this view, suggesting instead that under conditions of high interference, recognition memory impairments following medial temporal lobe damage arise because novel information appears as though it has been previously seen. Here, we developed a new object recognition memory paradigm that distinguished whether object recognition memory impairments were driven by previously viewed objects being treated as if they were novel or by novel objects falsely recognized as though they were previously seen. In this indirect, eyetracking-based passive viewing task, older adults at risk for mild cognitive impairment showed false recognition to high-interference novel items (with a significant degree of feature overlap with previously studied items) but normal novelty responses to low-interference novel items (with a lower degree of feature overlap). The indirect nature of the task minimized the effects of response bias and other memory-based decision processes, suggesting that these factors cannot solely account for false recognition. These findings support the counterintuitive notion that recognition memory impairments in this memory-impaired population are not characterized by forgetting but rather are driven by the failure to differentiate perceptually similar objects, leading to the false recognition of novel objects as having been seen before