Cerebellar Integrity in the Amyotrophic Lateral Sclerosis - Frontotemporal Dementia Continuum

Amyotrophic lateral sclerosis (ALS) and behavioural variant frontotemporal dementia (bvFTD) are multisystem neurodegenerative disorders that manifest overlapping cognitive, neuropsychiatric and motor features. The cerebellum has long been known to be crucial for intact motor function although emerging evidence over the past decade has attributed cognitive and neuropsychiatric processes to this structure. The current study set out i) to establish the integrity of cerebellar subregions in the amyotrophic lateral sclerosis-behavioural variant frontotemporal dementia spectrum (ALS-bvFTD) and ii) determine whether specific cerebellar atrophy regions are associated with cognitive, neuropsychiatric and motor symptoms in the patients. Seventy-eight patients diagnosed with ALS, ALS-bvFTD, behavioural variant frontotemporal dementia (bvFTD), most without C9ORF72 gene abnormalities, and healthy controls were investigated. Participants underwent cognitive, neuropsychiatric and functional evaluation as well as structural imaging using voxel-based morphometry (VBM) to examine the grey matter subregions of the cerebellar lobules, vermis and crus. VBM analyses revealed: i) significant grey matter atrophy in the cerebellum across the whole ALS-bvFTD continuum; ii) atrophy predominantly of the superior cerebellum and crus in bvFTD patients, atrophy of the inferior cerebellum and vermis in ALS patients, while ALS-bvFTD patients had both patterns of atrophy. Post-hoc covariance analyses revealed that cognitive and neuropsychiatric symptoms were particularly associated with atrophy of the crus and superior lobule, while motor symptoms were more associated with atrophy of the inferior lobules. Taken together, these findings indicate an important role of the cerebellum in the ALS-bvFTD disease spectrum, with all three clinical phenotypes demonstrating specific patterns of subregional atrophy that associated with different symptomology

Current experiences and educational preferences of general practitioners and staff caring for people with dementia living in residential facilities

<p>Abstract</p> <p>Background</p> <p>Residential care is important for older adults, particularly for those with advanced dementia and their families. Education interventions that achieve sustainable improvement in the care of older adults are critical to quality care. There are few systematic data available regarding the educational needs of Residential Care Facility (RCF) staff and General Practitioners (GPs) relating to dementia, or the sustainability of educational interventions. We sought to determine participation in dementia education, perceived levels of current knowledge regarding dementia, perceived unmet educational needs, current barriers, facilitators and preferences for dementia education.</p> <p>Methods</p> <p>A mixed methods study design was utilised. A survey was distributed to a convenience sample of general practitioners, and staff in 223 consecutive residential care facilities in Perth, Western Australia. Responses were received from 102 RCF staff working in 10 facilities (out of 33 facilities who agreed to distribute the survey) and 202 GPs (19% of metropolitan GPs). Quantitative survey data were summarised descriptively and chi squared statistics were used to analyse the distribution of categorical variables. Qualitative data were collected from general practitioners, staff in residential care facilities and family carers of people with dementia utilizing individual interviews, surveys and focus groups. Qualitative data were analysed thematically.</p> <p>Results</p> <p>Among RCF staff and GPs attending RCF, participation in dementia education was high, and knowledge levels generally perceived as good. The individual experiences and needs of people with dementia and their families were emphasised. Participants identified the need for a person centred philosophy to underpin educational interventions. Limited time was a frequently mentioned barrier, especially in relation to attending dementia care education. Perceived educational needs relating to behaviours of concern, communication, knowledge regarding dementia, aspects of person centred care, system factors and the multidisciplinary team were consistently and frequently cited. Small group education which is flexible, individualized, practical and case based was sought.</p> <p>Conclusion</p> <p>The effectiveness and sustainability of an educational intervention based on these findings needs to be tested. In addition, future interventions should focus on supporting cultural change to facilitate sustainable improvements in care.</p

The Origins of Novel Protein Interactions during Animal Opsin Evolution

Background. Biologists are gaining an increased understanding of the genetic bases of phenotypic change during evolution. Nevertheless, the origins of phenotypes mediated by novel protein-protein interactions remain largely undocumented. Methodology/Principle Findings. Here we analyze the evolution of opsin visual pigment proteins from the genomes of early branching animals, including a new class of opsins from Cnidaria. We combine these data with existing knowledge of the molecular basis of opsin function in a rigorous phylogenetic framework. We identify adaptive amino acid substitutions in duplicated opsin genes that correlate with a diversification of physiological pathways mediated by different protein-protein interactions. Conclusions/Significance. This study documents how gene duplication events early in the history of animals followed by adaptive structural mutations increased organismal complexity by adding novel protein-protein interactions that underlie different physiological pathways. These pathways are central to vision and other photo-reactive phenotypes in most extant animals. Similar evolutionary processes may have been a work in generating other metazoan sensory systems and other physiological processes mediated by signal transduction

Identification of Contractile Vacuole Proteins in Trypanosoma cruzi

Contractile vacuole complexes are critical components of cell volume regulation and have been shown to have other functional roles in several free-living protists. However, very little is known about the functions of the contractile vacuole complex of the parasite Trypanosoma cruzi, the etiologic agent of Chagas disease, other than a role in osmoregulation. Identification of the protein composition of these organelles is important for understanding their physiological roles. We applied a combined proteomic and bioinfomatic approach to identify proteins localized to the contractile vacuole. Proteomic analysis of a T. cruzi fraction enriched for contractile vacuoles and analyzed by one-dimensional gel electrophoresis and LC-MS/MS resulted in the addition of 109 newly detected proteins to the group of expressed proteins of epimastigotes. We also identified different peptides that map to at least 39 members of the dispersed gene family 1 (DGF-1) providing evidence that many members of this family are simultaneously expressed in epimastigotes. Of the proteins present in the fraction we selected several homologues with known localizations in contractile vacuoles of other organisms and others that we expected to be present in these vacuoles on the basis of their potential roles. We determined the localization of each by expression as GFP-fusion proteins or with specific antibodies. Six of these putative proteins (Rab11, Rab32, AP180, ATPase subunit B, VAMP1, and phosphate transporter) predominantly localized to the vacuole bladder. TcSNARE2.1, TcSNARE2.2, and calmodulin localized to the spongiome. Calmodulin was also cytosolic. Our results demonstrate the utility of combining subcellular fractionation, proteomic analysis, and bioinformatic approaches for localization of organellar proteins that are difficult to detect with whole cell methodologies. The CV localization of the proteins investigated revealed potential novel roles of these organelles in phosphate metabolism and provided information on the potential participation of adaptor protein complexes in their biogenesis

Falls and falls efficacy: the role of sustained attention in older adults

<p>Abstract</p> <p>Background</p> <p>Previous evidence indicates that older people allocate more of their attentional resources toward their gait and that the attention-related changes that occur during aging increase the risk of falls. The aim of this study was to investigate whether performance and variability in sustained attention is associated with falls and falls efficacy in older adults.</p> <p>Methods</p> <p>458 community-dwelling adults aged ≥ 60 years underwent a comprehensive geriatric assessment. Mean and variability of reaction time (RT), commission errors and omission errors were recorded during a fixed version of the Sustained Attention to Response Task (SART). RT variability was decomposed using the Fast Fourier Transform (FFT) procedure, to help characterise variability associated with the arousal and vigilance aspects of sustained attention.</p> <p>The number of self-reported falls in the previous twelve months, and falls efficacy (Modified Falls Efficacy Scale) were also recorded.</p> <p>Results</p> <p>Significant increases in the mean and variability of reaction time on the SART were significantly associated with both falls (p < 0.01) and reduced falls efficacy (p < 0.05) in older adults. An increase in omission errors was also associated with falls (p < 0.01) and reduced falls efficacy (p < 0.05). Upon controlling for age and gender affects, logistic regression modelling revealed that increasing variability associated with the vigilance (top-down) aspect of sustained attention was a retrospective predictor of falling (p < 0.01, OR = 1.14, 95% CI: 1.03 - 1.26) in the previous year and was weakly correlated with reduced falls efficacy in non-fallers (p = 0.07).</p> <p>Conclusions</p> <p>Greater variability in sustained attention is strongly correlated with retrospective falls and to a lesser degree with reduced falls efficacy. This cognitive measure may provide a novel and valuable biomarker for falls in older adults, potentially allowing for early detection and the implementation of preventative intervention strategies.</p

Adaptor protein-2 sigma subunit mutations causing familial hypocalciuric hypercalcaemia type 3 (FHH3) demonstrate genotype-phenotype correlations, codon bias and dominant-negative effects.

The adaptor protein-2 sigma subunit (AP2σ2) is pivotal for clathrin-mediated endocytosis of plasma membrane constituents such as the calcium-sensing receptor (CaSR). Mutations of the AP2σ2 Arg15 residue result in familial hypocalciuric hypercalcaemia type 3 (FHH3), a disorder of extracellular calcium (Ca(2+) o) homeostasis. To elucidate the role of AP2σ2 in Ca(2+) o regulation, we investigated 65 FHH probands, without other FHH-associated mutations, for AP2σ2 mutations, characterized their functional consequences and investigated the genetic mechanisms leading to FHH3. AP2σ2 mutations were identified in 17 probands, comprising 5 Arg15Cys, 4 Arg15His and 8 Arg15Leu mutations. A genotype-phenotype correlation was observed with the Arg15Leu mutation leading to marked hypercalcaemia. FHH3 probands harboured additional phenotypes such as cognitive dysfunction. All three FHH3-causing AP2σ2 mutations impaired CaSR signal transduction in a dominant-negative manner. Mutational bias was observed at the AP2σ2 Arg15 residue as other predicted missense substitutions (Arg15Gly, Arg15Pro and Arg15Ser), which also caused CaSR loss-of-function, were not detected in FHH probands, and these mutations were found to reduce the numbers of CaSR-expressing cells. FHH3 probands had significantly greater serum calcium (sCa) and magnesium (sMg) concentrations with reduced urinary calcium to creatinine clearance ratios (CCCR) in comparison with FHH1 probands with CaSR mutations, and a calculated index of sCa × sMg/100 × CCCR, which was ≥ 5.0, had a diagnostic sensitivity and specificity of 83 and 86%, respectively, for FHH3. Thus, our studies demonstrate AP2σ2 mutations to result in a more severe FHH phenotype with genotype-phenotype correlations, and a dominant-negative mechanism of action with mutational bias at the Arg15 residue