[Show abstract][Hide abstract] ABSTRACT: Background:
The use of multiple medicines (polypharmacy) is increasingly common in older people. Ensuring that patients receive the most appropriate combinations of medications (appropriate polypharmacy) is a significant challenge. The quality of evidence to support the effectiveness of interventions to improve appropriate polypharmacy is low. Systematic identification of mediators of behaviour change, using the Theoretical Domains Framework (TDF), provides a theoretically robust evidence base to inform intervention design. This study aimed to (1) identify key theoretical domains that were perceived to influence the prescribing and dispensing of appropriate polypharmacy to older patients by general practitioners (GPs) and community pharmacists, and (2) map domains to associated behaviour change techniques (BCTs) to include as components of an intervention to improve appropriate polypharmacy in older people in primary care.
Semi-structured interviews were conducted with members of each healthcare professional (HCP) group using tailored topic guides based on TDF version 1 (12 domains). Questions covering each domain explored HCPs' perceptions of barriers and facilitators to ensuring the prescribing and dispensing of appropriate polypharmacy to older people. Interviews were audio-recorded and transcribed verbatim. Data analysis involved the framework method and content analysis. Key domains were identified and mapped to BCTs based on established methods and discussion within the research team.
Thirty HCPs were interviewed (15 GPs, 15 pharmacists). Eight key domains were identified, perceived to influence prescribing and dispensing of appropriate polypharmacy: 'Skills', 'Beliefs about capabilities', 'Beliefs about consequences', 'Environmental context and resources', 'Memory, attention and decision processes', 'Social/professional role and identity', 'Social influences' and 'Behavioural regulation'. Following mapping, four BCTs were selected for inclusion in an intervention for GPs or pharmacists: 'Action planning', 'Prompts/cues', 'Modelling or demonstrating of behaviour' and 'Salience of consequences'. An additional BCT ('Social support or encouragement') was selected for inclusion in a community pharmacy-based intervention in order to address barriers relating to interprofessional working that were encountered by pharmacists.
Selected BCTs will be operationalised in a theory-based intervention to improve appropriate polypharmacy for older people, to be delivered in GP practice and community pharmacy settings. Future research will involve development and feasibility testing of this intervention.
Full-text · Article · Nov 2015 · Implementation Science
[Show abstract][Hide abstract] ABSTRACT: APOE ɛ4, the most significant genetic risk factor for Alzheimer disease (AD), may mask effects of other loci. We re-analyzed genome-wide association study (GWAS) data from the International Genomics of Alzheimer's Project (IGAP) Consortium in APOE ɛ4+ (10 352 cases and 9207 controls) and APOE ɛ4- (7184 cases and 26 968 controls) subgroups as well as in the total sample testing for interaction between a single-nucleotide polymorphism (SNP) and APOE ɛ4 status. Suggestive associations (P<1 × 10(-4)) in stage 1 were evaluated in an independent sample (stage 2) containing 4203 subjects (APOE ɛ4+: 1250 cases and 536 controls; APOE ɛ4-: 718 cases and 1699 controls). Among APOE ɛ4- subjects, novel genome-wide significant (GWS) association was observed with 17 SNPs (all between KANSL1 and LRRC37A on chromosome 17 near MAPT) in a meta-analysis of the stage 1 and stage 2 data sets (best SNP, rs2732703, P=5·8 × 10(-9)). Conditional analysis revealed that rs2732703 accounted for association signals in the entire 100-kilobase region that includes MAPT. Except for previously identified AD loci showing stronger association in APOE ɛ4+ subjects (CR1 and CLU) or APOE ɛ4- subjects (MS4A6A/MS4A4A/MS4A6E), no other SNPs were significantly associated with AD in a specific APOE genotype subgroup. In addition, the finding in the stage 1 sample that AD risk is significantly influenced by the interaction of APOE with rs1595014 in TMEM106B (P=1·6 × 10(-7)) is noteworthy, because TMEM106B variants have previously been associated with risk of frontotemporal dementia. Expression quantitative trait locus analysis revealed that rs113986870, one of the GWS SNPs near rs2732703, is significantly associated with four KANSL1 probes that target transcription of the first translated exon and an untranslated exon in hippocampus (P⩽1.3 × 10(-8)), frontal cortex (P⩽1.3 × 10(-9)) and temporal cortex (P⩽1.2 × 10(-11)). Rs113986870 is also strongly associated with a MAPT probe that targets transcription of alternatively spliced exon 3 in frontal cortex (P=9.2 × 10(-6)) and temporal cortex (P=2.6 × 10(-6)). Our APOE-stratified GWAS is the first to show GWS association for AD with SNPs in the chromosome 17q21.31 region. Replication of this finding in independent samples is needed to verify that SNPs in this region have significantly stronger effects on AD risk in persons lacking APOE ɛ4 compared with persons carrying this allele, and if this is found to hold, further examination of this region and studies aimed at deciphering the mechanism(s) are warranted.Molecular Psychiatry advance online publication, 17 March 2015; doi:10.1038/mp.2015.23.
Full-text · Article · Mar 2015 · Molecular Psychiatry
[Show abstract][Hide abstract] ABSTRACT: Introduction
The brain and plasma metabolome of APP/PS1 double transgenic mice and wild type littermates were profiled longitudinally (6, 8, 10, 12 and 18 months) by a targeted metabolomics approach. A total of 184 metabolites including amino acids, biogenic amines, phospholipids and acylcarnitines were quantified by ultra-high performance liquid chromatography–mass spectrometry (UPLC-MS).
Materials and methods
Whole mouse brain and fasting blood plasma samples were obtains from female APP/PS1dE9 mice (n = 8-9) and age-matched wild type littermate controls. Brains were lyophilized and milled to a fine powder, and 25 mg (± 0.5 mg) was added to 300 µL of solvent (85% ethanol:15% PBS buffer). Sample were sonicated (5 min), vortexed and centrifuged (10000g; 4°C; 5 min). Metabolites in mouse plasma and brain extract were quantified by an establish mass spectrometry method using the Biocrates AbsoluteIDQ p180 kit.
Multivariate statistical models employing orthogonal projection to latent structures-discriminant analysis easily discerned samples APP/PS1 and WT mice (R2≤0.994; Q2≤0.890). Biochemical pathway analysis found a disturbance in polyamine metabolism with concentrations of putrescine, spermidine and spermine significantly increasing in APP/PS1 mice brain at 6-8 months and plasma at 10-12 months (p<0.05). Startlingly 58 phosphatidylcholine (PCs) from a total of 72 measured were significantly increased (p< 0.05) in APP/PS1 mouse brain (8 months). Whilst 64 PCs from 73 measured significantly decreased (p<0.05) in APP/PS1 mouse plasma (12 months). 3 lysophosphatidylcholines (LysoPCs) and 5 sphingomyelins (SPHs) were elevated in APP/PS1 mouse brain at 8 months, while 9 LysoPCs and 3 SPHs were lower in APP/PS1 mouse plasma (p<0.05) at 12 months. Of the 40 acylcarnitines analysed, significant differences were observed for 18 acylcarnitines in both brain and plasma.
This study reveals important biochemical disturbances occurring in both the CNS and circulation over the lifespan of this transgenic animal model which could provide new information regarding the pathophysiology of AD.
[Show abstract][Hide abstract] ABSTRACT: Introduction
Metabolomic profiling of human blood is an active area of investigation for the discovery of new diagnostic and prognostic tools for neurodegenerative disease. However, there is scant information regarding the effects of aging on the blood metabolome, particularly in elderly subjects. Such information is needed to ensure the validity and reproducibility of future metabolite biomarkers. This study measured the concentrations of 184 blood metabolites in 20 non-cognitively impaired elderly participants (T0; 78.3±1.7 yrs; MMSE= 29.13±0.21). The same 20 subjects were subsequently followed-up and resampled approximately five years later (T5; 83.6±1.69 yrs; MMSE= 26.86±0.53).
Materials and methods
Metabolites in plasma samples were quantified through an established mass spectrometry method employing the Biocrates AbsoluteIDQ p180 kit. The samples were analysed using a triple-quadrupole mass spectrometer (Xevo TQ-MS, Waters Corporation, USA). This was undertaken in a 96-well format, and included seven calibration standards. Human EDTA plasma samples spiked with standard metabolites were used as quality control samples to assess reproducibility of the assay. Statistical significance was determined by Wilcoxon matched-pairs signed rank test.
Partial least squares-discriminant analysis scores plot demonstrated that metabolomic profiles of plasma samples collected 5 years (T5) were distinctly different (R2=0.95; Q2=0.90) from the baseline (T0). In total 68 out of the 73 measured phosphatidylcholines (PCs) were significantly increased (p<0.05) in plasma at T5. Three lysophosphatidylcholine species (LysoPCs) and two sphingomyelins were significantly lower in plasma at T5. Two LysoPCs were higher (p<0.05) at T5. Of the 40 acylcarnitines measured, 25 were significantly higher (p<0.05) at T5. Furthermore, a total of 19 amino acid concentrations were significantly different (p<0.05) between the two time points.
This study shows that the levels of some classes of metabolites are significantly changed by advancing age and this must be taken into account in the selection of metabolites as biomarkers.
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND:
Late-onset Alzheimer's disease (AD) is heritable with 20 genes showing genome-wide association in the International Genomics of Alzheimer's Project (IGAP). To identify the biology underlying the disease, we extended these genetic data in a pathway analysis.
The ALIGATOR and GSEA algorithms were used in the IGAP data to identify associated functional pathways and correlated gene expression networks in human brain.
ALIGATOR identified an excess of curated biological pathways showing enrichment of association. Enriched areas of biology included the immune response (P = 3.27 × 10-12 after multiple testing correction for pathways), regulation of endocytosis (P = 1.31 × 10-11), cholesterol transport (P = 2.96 × 10-9), and proteasome-ubiquitin activity (P = 1.34 × 10-6). Correlated gene expression analysis identified four significant network modules, all related to the immune response (corrected P = .002-.05).
The immune response, regulation of endocytosis, cholesterol transport, and protein ubiquitination represent prime targets for AD therapeutics.
Full-text · Article · Dec 2014 · Alzheimer's and Dementia
[Show abstract][Hide abstract] ABSTRACT: No studies have been conducted in the UK context to date that categorise medications in terms of appropriateness for patients with advanced dementia, or that examine medication use in these vulnerable patients.
The objectives of this study were to categorise the appropriateness of a comprehensive list of medications and medication classes for use in patients with advanced dementia; examine the feasibility of conducting a longitudinal prospective cohort study to collect clinical and medication use data; and determine the appropriateness of prescribing for nursing home residents with advanced dementia in Northern Ireland (NI), using the categories developed.
A three-round Delphi consensus panel survey of expert clinicians was used to categorise the appropriateness of medications for patients with advanced dementia [defined as having Functional Assessment Staging (FAST) scores ranging from 6E to 7F]. This was followed by a longitudinal prospective cohort feasibility study that was conducted in three nursing homes in NI. Clinical and medication use for participating residents with advanced dementia (FAST scores ranging from 6E to 7F) were collected and a short test of dementia severity administered. These data were collected at baseline and every 3 months for up to 9 months or until death. For those residents who died during the study period, data were also collected within 14 days of death. The appropriateness ratings from the consensus panel survey were retrospectively applied to residents' medication data at each data collection timepoint to determine the appropriateness of medications prescribed for these residents.
Consensus was achieved for 87 (90 %) of the 97 medications and medication classes included in the survey. Fifteen residents were recruited to participate in the longitudinal prospective cohort feasibility study, four of whom died during the data collection period. Mean numbers of medications prescribed per resident were 16.2 at baseline, 19.6 at 3 months, 17.4 at 6 months and 16.1 at 9 months. Fourteen residents at baseline were taking at least one medication considered by the consensus panel to be never appropriate, and approximately 25 % of medications prescribed were considered to be never appropriate. Post-death data collection indicated a decrease in the proportion of never appropriate medications and an increase in the proportion of always appropriate medications for those residents who died.
This study is the first to develop and apply medication appropriateness indicators for patients with advanced dementia in the UK setting. The Delphi consensus panel survey of expert clinicians was a suitable method of developing such indicators. It is feasible to collect information on quality of life, functional performance, physical comfort, neuropsychiatric symptoms and cognitive function for this subpopulation of nursing home residents with advanced dementia.
[Show abstract][Hide abstract] ABSTRACT: Although epidemiological studies suggest that type 2 diabetes mellitus (T2DM) increases the risk of late-onset Alzheimer's disease (LOAD), the biological basis of this relationship is not well understood. The aim of this study was to examine the genetic comorbidity between the 2 disorders and to investigate whether genetic liability to T2DM, estimated by a genotype risk scores based on T2DM associated loci, is associated with increased risk of LOAD. This study was performed in 2 stages. In stage 1, we combined genotypes for the top 15 T2DM-associated polymorphisms drawn from approximately 3000 individuals (1349 cases and 1351 control subjects) with extracted and/or imputed data from 6 genome-wide studies (>10,000 individuals; 4507 cases, 2183 controls, 4989 population controls) to form a genotype risk score and examined if this was associated with increased LOAD risk in a combined meta-analysis. In stage 2, we investigated the association of LOAD with an expanded T2DM score made of 45 well-established variants drawn from the 6 genome-wide studies. Results were combined in a meta-analysis. Both stage 1 and stage 2 T2DM risk scores were not associated with LOAD risk (odds ratio = 0.988; 95% confidence interval, 0.972-1.004; p = 0.144 and odds ratio = 0.993; 95% confidence interval, 0.983-1.003; p = 0.149 per allele, respectively). Contrary to expectation, genotype risk scores based on established T2DM candidates were not associated with increased risk of LOAD. The observed epidemiological associations between T2DM and LOAD could therefore be a consequence of secondary disease processes, pleiotropic mechanisms, and/or common environmental risk factors. Future work should focus on well-characterized longitudinal cohorts with extensive phenotypic and genetic data relevant to both LOAD and T2DM.
Full-text · Article · Jul 2014 · Neurobiology of Aging
[Show abstract][Hide abstract] ABSTRACT: Background: Alzheimer’s disease is a common debilitating dementia with known heritability, for which 20 late onset susceptibility loci have been identified, but more remain to be discovered. This study sought to identify new susceptibility genes, using an alternative gene-wide analytical approach which tests for patterns of association within genes, in the powerful genome-wide association dataset of the International Genomics of Alzheimer’s Project Consortium, comprising over 7 m genotypes from 25,580 Alzheimer’s cases and 48,466 controls.
Principal Findings: In addition to earlier reported genes, we detected genome-wide significant loci on chromosomes 8 (TP53INP1, p=1.461026) and 14 (IGHV1-67 p=7.961028) which indexed novel susceptibility loci.
Significance: The additional genes identified in this study, have an array of functions previously implicated in Alzheimer’s disease, including aspects of energy metabolism, protein degradation and the immune system and add further weight to these pathways as potential therapeutic targets in Alzheimer’s disease
[Show abstract][Hide abstract] ABSTRACT: Disease-, age- and gender-associated changes in brain copper, iron and zinc were assessed in post-mortem neocortical tissue (Brodmann area 7) from patients with moderate Alzheimer’s disease (AD) (n=14), severe AD (n=28), dementia with Lewy Bodies (DLB) (n=15) and normal age-matched control subjects (n=26). Copper was lower (20%; P<0.001) and iron higher (10-16%; P<0.001) in severe AD compared with Control. Intriguingly significant Group*Age interactions were observed for both copper and iron, suggesting gradual age-associated decline of these metals in healthy non-cognitively impaired individuals. Zinc was unaffected in any disease pathologies and no age-associated changes were apparent. Age-associated changes in brain elements warrant further investigation.
Full-text · Article · May 2014 · Journal of Alzheimer's disease: JAD
[Show abstract][Hide abstract] ABSTRACT: Alzheimer's disease (AD) is the most common and complex neurodegenerative disease in the elderly individuals. Recently, genome-wide association studies (GWAS) have been used to investigate AD pathogenesis. These GWAS have yielded important new insights into the genetic mechanisms of AD. However, these newly identified AD susceptibility loci exert only very small risk effects and cannot fully explain the underlying AD genetic risk. We hypothesize that combining the findings from different AD GWAS may have greater power than genetic analysis alone. To identify new AD risk factors, we integrated findings from 3 previous large-scale AD GWAS (n = 14,138) using a gene-based meta-analysis and subsequently conducted a pathway analysis using the kyoto encyclopedia of genes and genomes and gene ontology databases. Interestingly, we not only confirmed previous findings, but also highlighted, for the first time, the involvement of cardiovascular disease-related pathways in AD. Our results provided the clues as to the link between these diseases using pathway analysis methods. We believe that these findings will be very useful for future genetic studies of AD.
[Show abstract][Hide abstract] ABSTRACT: Eleven susceptibility loci for late-onset Alzheimer's disease (LOAD) were identified by previous studies; however, a large portion of the genetic risk for this disease remains unexplained. We conducted a large, two-stage meta-analysis of genome-wide association studies (GWAS) in individuals of European ancestry. In stage 1, we used genotyped and imputed data (7,055,881 SNPs) to perform meta-analysis on 4 previously published GWAS data sets consisting of 17,008 Alzheimer's disease cases and 37,154 controls. In stage 2, 11,632 SNPs were genotyped and tested for association in an independent set of 8,572 Alzheimer's disease cases and 11,312 controls. In addition to the APOE locus (encoding apolipoprotein E), 19 loci reached genome-wide significance (P < 5 × 10(-8)) in the combined stage 1 and stage 2 analysis, of which 11 are newly associated with Alzheimer's disease.
[Show abstract][Hide abstract] ABSTRACT: ABSTRACT Challenges to pharmacological management in this patient group include treatment concordance, comorbidity, polypharmacy, and age-related physiological changes affecting pharmacokinetics. Paracetamol (acetaminophen) is generally recommended as a first-choice analgesic in osteoarthritis pain. Topical nonsteroidal anti-inflammatory drugs (NSAIDs) should be considered ahead of oral formulations, and prescribing NSAIDs for older people requires careful consideration. There are some data relating to opioid use for noncancer pain in older people.
No preview · Article · Aug 2013 · Journal of Pain & Palliative Care Pharmacotherapy