Current Developments in Dementia Risk Prediction Modelling: An Updated Systematic Review

Background

Accurate identification of individuals at high risk of dementia influences clinical care, inclusion criteria for clinical trials and development of preventative strategies. Numerous models have been developed for predicting dementia. To evaluate these models we undertook a systematic review in 2010 and updated this in 2014 due to the increase in research published in this area. Here we include a critique of the variables selected for inclusion and an assessment of model prognostic performance.

Methods

Our previous systematic review was updated with a search from January 2009 to March 2014 in electronic databases (MEDLINE, Embase, Scopus, Web of Science). Articles examining risk of dementia in non-demented individuals and including measures of sensitivity, specificity or the area under the curve (AUC) or c-statistic were included.

Findings

In total, 1,234 articles were identified from the search; 21 articles met inclusion criteria. New developments in dementia risk prediction include the testing of non-APOE genes, use of non-traditional dementia risk factors, incorporation of diet, physical function and ethnicity, and model development in specific subgroups of the population including individuals with diabetes and those with different educational levels. Four models have been externally validated. Three studies considered time or cost implications of computing the model.

Interpretation

There is no one model that is recommended for dementia risk prediction in population-based settings. Further, it is unlikely that one model will fit all. Consideration of the optimal features of new models should focus on methodology (setting/sample, model development and testing in a replication cohort) and the acceptability and cost of attaining the risk variables included in the prediction score. Further work is required to validate existing models or develop new ones in different populations as well as determine the ethical implications of dementia risk prediction, before applying the particular models in population or clinical settings.     

Support for the habitat amount hypothesis from a global synthesis of species density studies

Decades of research suggest that species richness depends on spatial characteristics of habitat patches, especially their size and isolation. In contrast, the habitat amount hypothesis predicts that (1) species richness in plots of fixed size (species density) is more strongly and positively related to the amount of habitat around the plot than to patch size or isolation; (2) habitat amount better predicts species density than patch size and isolation combined, (3) there is no effect of habitat fragmentation per se on species density and (4) patch size and isolation effects do not become stronger with declining habitat amount. Data on eight taxonomic groups from 35 studies around the world support these predictions. Conserving species density requires minimising habitat loss, irrespective of the configuration of the patches in which that habitat is contained.     

LIGHT AND ELECTRON MICROSCOPY OF THE RESIN GLANDS OF PASSIFLORA FOETIDA (PASSIFLORACEAE)

Petiolar, bracteolar, and stipular glands from two varieties of Passiflora foetida were studied by both light and electron microscopy. These glands have previously been called nectaries. They do resemble the sugar-secreting glands of other Passiflora species with respect to their location and morphology. However, cytological studies together with chemical tests of the exudate support the view that the glands in the varieties studied actually secrete a resin-like substance which possibly functions as an anti-herbivore mechanism.     

Reticulon short hairpin transmembrane domains are used to shape ER tubules

Reticulons are integral membrane proteins that partition into and shape the tubular endoplasmic reticulum (ER). We propose that reticulons use a membrane insertion mechanism to generate regions of high membrane curvature in the ER. A reticulon contains two short hairpin transmembrane domains (TMDs), which could generate membrane curvature by increasing the area of the cytoplasmic leaflet. Here, we test whether the short length of these hairpin TMDs is required for reticulon membrane-shaping functions in mammalian cells. We lengthened the TMDs of reticulon 4 to resemble a typical bi-pass TMD that spans both leaflets. We find that TMD mutants oligomerize like wild type (wt), however, they are not immobilized, do not partition into tubules, do not constrict tubules and no longer suppress peripheral ER cisternae. Therefore, short hairpin TMD length is required for reticulon protein partitioning and membrane-shaping functions. Another membrane protein with a short hairpin TMD is caveolin. We show that an ER-retained caveolin construct also partitions within the ER in a manner that is dependent on it containing a short hairpin TMD. These data suggest that a short hairpin TMD may be a general feature used by membrane-shaping proteins to partition into and shape regions of high membrane curvature.     

Genome-wide association analysis identifies variants associated with nonalcoholic fatty liver disease that have distinct effects on metabolic traits

Nonalcoholic fatty liver disease (NAFLD) clusters in families, but the only known common genetic variants influencing risk are near PNPLA3. We sought to identify additional genetic variants influencing NAFLD using genome-wide association (GWA) analysis of computed tomography (CT) measured hepatic steatosis, a non-invasive measure of NAFLD, in large population based samples. Using variance components methods, we show that CT hepatic steatosis is heritable (∼26%–27%) in family-based Amish, Family Heart, and Framingham Heart Studies (n = 880 to 3,070). By carrying out a fixed-effects meta-analysis of genome-wide association (GWA) results between CT hepatic steatosis and ∼2.4 million imputed or genotyped SNPs in 7,176 individuals from the Old Order Amish, Age, Gene/Environment Susceptibility-Reykjavik study (AGES), Family Heart, and Framingham Heart Studies, we identify variants associated at genome-wide significant levels (p<5×10⁻⁸) in or near PNPLA3, NCAN, and PPP1R3B. We genotype these and 42 other top CT hepatic steatosis-associated SNPs in 592 subjects with biopsy-proven NAFLD from the NASH Clinical Research Network (NASH CRN). In comparisons with 1,405 healthy controls from the Myocardial Genetics Consortium (MIGen), we observe significant associations with histologic NAFLD at variants in or near NCAN, GCKR, LYPLAL1, and PNPLA3, but not PPP1R3B. Variants at these five loci exhibit distinct patterns of association with serum lipids, as well as glycemic and anthropometric traits. We identify common genetic variants influencing CT–assessed steatosis and risk of NAFLD. Hepatic steatosis associated variants are not uniformly associated with NASH/fibrosis or result in abnormalities in serum lipids or glycemic and anthropometric traits, suggesting genetic heterogeneity in the pathways influencing these traits.     

Isolation of human proteasomes and putative proteasome-interacting proteins using a novel affinity chromatography method

The proteasome is the primary subcellular organelle responsible for protein degradation. It is a dynamic assemblage of 34 core subunits and many differentially expressed, transiently interacting, modulatory proteins. This paper describes a novel affinity chromatography method for the purification of functional human holoproteasome complexes using mild conditions. Human proteasomes purified by this simple procedure maintained the ability to proteolytically process synthetic peptide substrates and degrade ubiquitinated parkin. Furthermore, the entire purification fraction was analyzed by mass spectrometry in order to identify proteasomal proteins and putative proteasome-interacting proteins. The mild purification conditions maintained transient physical interactions between holoproteasomes and a number of known modulatory proteins. In addition, several classes of putative interacting proteins co-purified with the proteasomes, including proteins with a role in the ubiquitin proteasome system for protein degradation or DNA repair. These results demonstrate the efficacy of using this affinity purification strategy for isolating functional human proteasomes and identifying proteins that may physically interact with human proteasomes.     

Landscape moderation of biodiversity patterns and processes - eight hypotheses

Understanding how landscape characteristics affect biodiversity patterns and ecological processes at local and landscape scales is critical for mitigating effects of global environmental change. In this review, we use knowledge gained from human-modified landscapes to suggest eight hypotheses, which we hope will encourage more systematic research on the role of landscape composition and configuration in determining the structure of ecological communities, ecosystem functioning and services. We organize the eight hypotheses under four overarching themes. Section A: 'landscape moderation of biodiversity patterns' includes (1) the landscape species pool hypothesis-the size of the landscape-wide species pool moderates local (alpha) biodiversity, and (2) the dominance of beta diversity hypothesis-landscape-moderated dissimilarity of local communities determines landscape-wide biodiversity and overrides negative local effects of habitat fragmentation on biodiversity. Section B: 'landscape moderation of population dynamics' includes (3) the cross-habitat spillover hypothesis-landscape-moderated spillover of energy, resources and organisms across habitats, including between managed and natural ecosystems, influences landscape-wide community structure and associated processes and (4) the landscape-moderated concentration and dilution hypothesis-spatial and temporal changes in landscape composition can cause transient concentration or dilution of populations with functional consequences. Section C: 'landscape moderation of functional trait selection' includes (5) the landscape-moderated functional trait selection hypothesis-landscape moderation of species trait selection shapes the functional role and trajectory of community assembly, and (6) the landscape-moderated insurance hypothesis-landscape complexity provides spatial and temporal insurance, i.e. high resilience and stability of ecological processes in changing environments. Section D: 'landscape constraints on conservation management' includes (7) the intermediate landscape-complexity hypothesis-landscape-moderated effectiveness of local conservation management is highest in structurally simple, rather than in cleared (i.e. extremely simplified) or in complex landscapes, and (8) the landscape-moderated biodiversity versus ecosystem service management hypothesis-landscape-moderated biodiversity conservation to optimize functional diversity and related ecosystem services will not protect endangered species. Shifting our research focus from local to landscape-moderated effects on biodiversity will be critical to developing solutions for future biodiversity and ecosystem service management.     

Tn5386, a novel Tn916-like mobile element in Enterococcus faecium D344R that interacts with Tn916 to yield a large genomic deletion

We describe Tn5386, a novel ca.-29-kb Tn916-like mobile element discovered to occur in ampicillin-resistant, Tn916-containing Enterococcus faecium D344R. PCR amplification experiments after overnight growth with or without tetracycline revealed "joint" regions of circularized Tn5386 composed of 6-bp sequences linking different transposon termini. In one case (no tetracycline), the termini were consistent with those derived by target site analysis of the integrated element. In the other case, the termini were virtually identical in distance from the integrase binding regions, as seen with Tn916. These data are consistent with a model in which one PCR product results from the action of Tn5386 integrase, whereas the other results from the action of the Tn916 integrase on Tn5386. Spontaneous conversion of D344R to an ampicillin-susceptible phenotype (D344SRF) was associated with a 178-kb deletion extending from the left end of Tn5386 to the left end of Tn916. Examination of the Tn5386 junction after the large deletion event suggests that the deletion resulted from an interaction between the nonintegrase ends of Tn5386 and Tn916. The terminus of Tn5386 identified in this reaction suggested that it may have resulted from the activity of the Tn916 integrase (Int(Tn916)). The "joint" of the circular element resulting from this excision was amplifiable from D344R, the sequence of which revealed a heteroduplex consistent with Int(Tn916)-mediated excision. In contrast, Tn5386 joints amplified from ampicillin-susceptible D344SRF revealed ends consistent with Tn5386 integrase activity, reflecting the absence of Tn916 from this strain. Tn5386 represents a new member of the Tn916 transposon family. Our data suggest that excision of Tn5386 can be catalyzed by the Tn916 integrase and that large genomic deletions may result from the interaction between these heterologous elements.     

Embodied changes and the search for gynecological cancer diagnosis

The detection and successful treatment of cancers is dependent on timely presentation with abnormal and often subtle symptoms. In this article, we draw on research conducted with Australian immigrant women in 2001-02 who experienced delays in diagnosis of gynecological cancer. Data from in-depth interviews with women with gynecological cancer indicated a common trajectory of an "illness career" whereby the search for diagnosis was often painful and lengthy, either because women normalized the abnormal signs or because their experiences of bodily abnormality, pain, and dysfunction contrasted with medical explanations. This delay was sometimes exacerbated by structural barriers. As a result, diagnosis was often protracted, during which time women presented with symptoms that were dismissed or resulted in the misdiagnosis, with a resultant loss of confidence in clinical services.