Complex phenotypic analysis to identify genes which contribute to or modify the development of Alzheimer's disease.

Late-onset Alzheimer's disease (LOAD) is a heritable disorder. It is invariably characterised by a decline in cognitive abilities, however, marked variation in behavioural symptoms and age at onset are observed between sufferers. This clinical heterogeneity may be genetically modified, hence, may provide a productive avenue of exploration for those seeking to unravel the genetic aetiology of LOAD. This thesis employed a sequential three stage approach to search for loci implicated in the development of genetically influenced features of the disease. Behavioural symptoms in 1,120 unrelated individuals with LOAD were assessed using the Neuropsychiatric Inventory. The 12 symptom domain scores were subjected to principal components analysis. Three interpretable components were identified, comprising: "frontal lobe dysfunction", "psychosis" and "mood". These components remained stable when taking account of disease severity. The familiality of clinical variation was assessed. Affected siblings from 388 families were characterised in terms of aggression, psychosis and mood disturbances. Age at onset data were available for affected siblings from 458 families. Familial clustering was found for age at onset, psychosis, aggression and mild depression, with the strongest evidence noted for age at onset and psychosis. Major depression and a combined phenotype of depression with anxiety showed limited evidence of familial aggregation. Covariate linkage analysis was employed to search for loci which may influence clinical variation in LOAD. This included a sample of 513 affected relative pairs. Increases in LOD were observed with age at onset (chromosome 1, 2,12,19 and 21), aggression (chromosome 9), psychosis (chromosome 7 and 15) and minor depression (chromosome 21). Understanding factors associated with behavioural symptoms and age at disease onset may lead to the achievable goal of disease modification. These findings support the hypothesis that clinical variation in AD is genetically modified, setting the stage for future linkage and association studies

Genes of the serotonergic and dopaminergic pathways and their interaction affect the expression of Behavioural and Psychological Symptoms in Dementia (BPSD).

Although there is evidence for the involvement of genes of serotonergic and dopaminergic systems in the manifestation of the Behavioural and Psychological Symptoms in Dementia (BPSD), genetic association studies are contradictory. We used 1008 probable AD patients from the UK and applied a Multiple Indicators Multiple Causes (MIMIC) approach to investigate the effect of 11 polymorphisms in the serotonergic and dopaminergic systems, on four behavioural sub-phenotypes, namely "psychosis"," moods", "agitation" and "behavioural dyscontrol", as well as on 12 NPI items. Significant findings included the association of DRD1 A48G with "psychosis" (p=0.037), the association of DAT1 VNTR with "agitation" (p=0.006) and the association of DRD4 with "moods" sub-phenotype (p=0.008). In addition, associations were identified between DRD1 A48G and DAT1 VNTR with aberrant motor behaviour (AMB) symptoms (p=0.001 and p=0.015 respectively), between DRD4 and sleep disturbances (p=0.018) and between 5HTTLPR and apathy (p=0.033). Finally, significant interactions were observed between COMT Val158Met and 5HTTLPR with "psychosis" (p=0.026), between HTTLPR and STin2 with "psychosis" (p=0.005), between DAT1 3'UTR VNTR and COMT Val158Met with "agitation" (p=0.0001) and between DAT1 3'UTR VNTR and 5HTTLPR with the "moods" factor (p=0.0027). The complexity of the interrelations between genetic variation, behavioural symptoms and clinical variables was efficiently captured by this MIMIC model

Verbal fluency as a quick and simple tool to help in deciding when to refer patients with a possible brain tumour

BACKGROUND: Patients with brain tumours often present with non-specific symptoms. Correctly identifying who to prioritise for urgent brain imaging is challenging. Brain tumours are amongst the commonest cancers diagnosed as an emergency presentation. A verbal fluency task (VFT) is a rapid triage test affected by disorders of executive function, language and processing speed. We tested whether a VFT could support identification of patients with a brain tumour. METHODS: This proof-of-concept study examined whether a VFT can help differentiate patients with a brain tumour from those with similar symptoms (i.e. headache) without a brain tumour. Two patient populations were recruited, (a) patients with known brain tumour, and (b) patients with headache referred for Direct-Access Computed-Tomography (DACT) from primary care with a suspicion of a brain tumour. Semantic and phonemic verbal fluency data were collected prospectively. RESULTS: 180 brain tumour patients and 90 DACT patients were recruited. Semantic verbal fluency score was significantly worse for patients with a brain tumour than those without (P  <  0.001), whether comparing patients with headache, or patients without headache. Phonemic fluency showed a similar but weaker difference. Raw and incidence-weighted positive and negative predictive values were calculated. CONCLUSION: We have demonstrated the potential role of adding semantic VFT score performance into clinical decision making to support triage of patients for urgent brain imaging. A relatively small improvement in the true positive rate in patients referred for DACT has the potential to increase the timeliness and efficiency of diagnosis and improve patient outcomes. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12883-022-02655-9

Long-term impact of the expansion of a hospital liaison psychiatry service on patient care and costs following emergency department attendances for self-harm

BACKGROUND: In September 2014, as part of a national initiative to increase access to liaison psychiatry services, the liaison psychiatry services at Bristol Royal Infirmary received new investment of £250 000 per annum, expanding its availability from 40 to 98 h per week. The long-term impact on patient outcomes and costs, of patients presenting to the emergency department with self-harm, is unknown. AIMS: To assess the long-term impact of the investment on patient care outcomes and costs, of patients presenting to the emergency department with self-harm. METHOD: Monthly data for all self-harm emergency department attendances between 1 September 2011 and 30 September 2017 was modelled using Bayesian structural time series to estimate expected outcomes in the absence of expanded operating hours (the counterfactual). The difference between the observed and expected trends for each outcome were interpreted as the effects of the investment. RESULTS: Over the 3 years after service expansion, the mean number of self-harm attendances increased 13%. Median waiting time from arrival to psychosocial assessment was 2 h shorter (18.6% decrease, 95% Bayesian credible interval (BCI) −30.2% to −2.8%), there were 45 more referrals to other agencies (86.1% increase, 95% BCI 60.6% to 110.9%) and a small increase in the number of psychosocial assessments (11.7% increase, 95% BCI −3.4% to 28.5%) per month. Monthly mean net hospital costs were £34 more per episode (5.3% increase, 95% BCI −11.6% to 25.5%). CONCLUSIONS: Despite annual increases in emergency department attendances, investment was associated with reduced waiting times for psychosocial assessment and more referrals to other agencies, with only a small increase in cost per episode

Language and memory for object location

In three experiments, we investigated the influence of two types of language on memory for object location: demonstratives (this, that) and possessives (my, your). Participants first read instructions containing demonstratives/possessives to place objects at different locations, and then had to recall those object locations (following object removal). Experiments 1 and 2 tested contrasting predictions of two possible accounts of language on object location memory: the Expectation Model (Coventry, Griffiths, & Hamilton, 2014) and the congruence account (Bonfiglioli, Finocchiaro, Gesierich, Rositani, & Vescovi, 2009). In Experiment 3, the role of attention allocation as a possible mechanism was investigated. Results across all three experiments show striking effects of language on object location memory, with the pattern of data supporting the Expectation Model. In this model, the expected location cued by language and the actual location are concatenated leading to (mis)memory for object location, consistent with models of predictive coding (Bar, 2009; Friston, 2003)

Evaluating complex interventions in end of life care: the MORECare statement on good practice generated by a synthesis of transparent expert consultations and systematic reviews.

BACKGROUND: Despite being a core business of medicine, end of life care (EoLC) is neglected. It is hampered by research that is difficult to conduct with no common standards. We aimed to develop evidence-based guidance on the best methods for the design and conduct of research on EoLC to further knowledge in the field. METHODS: The Methods Of Researching End of life Care (MORECare) project built on the Medical Research Council guidance on the development and evaluation of complex circumstances. We conducted systematic literature reviews, transparent expert consultations (TEC) involving consensus methods of nominal group and online voting, and stakeholder workshops to identify challenges and best practice in EoLC research, including: participation recruitment, ethics, attrition, integration of mixed methods, complex outcomes and economic evaluation. We synthesised all findings to develop a guidance statement on the best methods to research EoLC. RESULTS: We integrated data from three systematic reviews and five TECs with 133 online responses. We recommend research designs extending beyond randomised trials and encompassing mixed methods. Patients and families value participation in research, and consumer or patient collaboration in developing studies can resolve some ethical concerns. It is ethically desirable to offer patients and families the opportunity to participate in research. Outcome measures should be short, responsive to change and ideally used for both clinical practice and research. Attrition should be anticipated in studies and may affirm inclusion of the relevant population, but careful reporting is necessitated using a new classification. Eventual implementation requires consideration at all stages of the project. CONCLUSIONS: The MORECare statement provides 36 best practice solutions for research evaluating services and treatments in EoLC to improve study quality and set the standard for future research. The statement may be used alongside existing statements and provides a first step in setting common, much needed standards for evaluative research in EoLC. These are relevant to those undertaking research, trainee researchers, research funders, ethical committees and editors.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are