[Show abstract][Hide abstract] ABSTRACT: Background:
Nursing home patients have complex mental and physical health problems, disabilities and social needs, combined with widespread prescription of psychotropic drugs. Preservation of their quality of life is an important goal. This can only be achieved within nursing homes that offer competent clinical conditions of treatment and care. COmmunication, Systematic assessment and treatment of pain, Medication review, Occupational therapy, Safety (COSMOS) is an effectiveness-implementation hybrid trial that combines and implements organization of activities evidence-based interventions to improve staff competence and thereby the patients' quality of life, mental health and safety. The aim of this paper is to describe the development, content and implementation process of the COSMOS trial.
COSMOS includes a 2-month pilot study with 128 participants distributed among nine Norwegian nursing homes, and a 4-month multicenter, cluster randomized effectiveness-implementation clinical hybrid trial with follow-up at month 9, including 571 patients from 67 nursing home units (one unit defined as one cluster). Clusters are randomized to COSMOS intervention or current best practice (control group). The intervention group will receive a 2-day education program including written guidelines, repeated theoretical and practical training (credited education of caregivers, physicians and nursing home managers), case discussions and role play. The 1-day midway evaluation, information and interviews of nursing staff and a telephone hotline all support the implementation process. Outcome measures include quality of life in late-stage dementia, neuropsychiatric symptoms, activities of daily living, pain, depression, sleep, medication, cost-utility analysis, hospital admission and mortality.
Despite complex medical and psychosocial challenges, nursing home patients are often treated by staff possessing low level skills, lacking education and in facilities with a high staff turnover. Implementation of a research-based multicomponent intervention may improve staff's knowledge and competence and consequently the quality of life of nursing home patients in general and people with dementia in particular.
[Show abstract][Hide abstract] ABSTRACT: The unfolded protein response (UPR) is a pro-survival defense mechanism induced during periods of endoplasmic reticulum stress, and it has recently emerged as an attractive therapeutic target across a number of neurodegenerative conditions, but has not yet been studied in synuclein disorders.
The level of a key mediator of the UPR pathway, glucose regulated protein 78 (GRP78), also known as binding immunoglobulin protein (BiP), was measured in post-mortem brain tissue of patients with dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD) in comparison to Alzheimer's disease (AD) and age matched controls using western blot. The UPR activation was further confirmed by immunohistochemical detection of GRP78/BiP and phosphorylated protein kinase RNA-like ER kinase (p-PERK).
GRP78/BiP was increased to a greater extent in DLB and PDD patients compared to AD and control subjects in cingulate gyrus and parietal cortex. However, there were no changes in the prefrontal and temporal cortices. There was a significant positive correlation between GRP78/BiP level and α-synuclein pathology in the cingulate gyrus, while AD-type pathology showed an inverse correlation relationship in the parietal cortex.
Overall, these results give emphasis to the role of UPR in Lewy body dementias, and suggest that Lewy body degeneration, in combination with AD-type pathologies, is associated with increased UPR activation to a greater extent than AD alone, possibly as a consequence of the increasing load of ER proteins. This work also highlights a novel opportunity to explore the UPR as a therapeutic target in synuclein diseases.
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Neuropathology and Applied Neurobiology 07/2015; DOI:10.1111/nan.12260 · 3.93 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objectives
This paper reports on the acceptability and effectiveness of the FITS into Practice Programme which was scaled up from an intervention that had proven significant results from an earlier cluster randomised controlled trial.
An in depth ten-day education course in person-centred care was delivered over a three-month period and followed by 6 supervision sessions. Participants were care-home staff designated as Dementia Care Coaches (DCCs) responsible for implementing interventions in their home. The course and supervision was provided by educators called Dementia Practice Development Coaches (DPDCs).
Effectiveness data included monitoring antipsychotic prescriptions, goal attainment, knowledge, attitude and implementation questionnaires. Qualitative data elucidated issues of implementation.
Of the 100 DCCs recruited, 66 DCCs completed the programme. Pre-post questionnaires demonstrated increased knowledge and confidence and improved attitudes to dementia. 20.1% of residents were prescribed antipsychotics at baseline which reduced to 13.9% (30.5% reduction) with additional dose reductions being reported alongside improved personalised goal attainment. Crucial for FITS into Practice to succeed was the allocation and protection of time for the DCC to attend training and supervision and to carry out implementation tasks in addition to their existing job role. Evaluation data showed that this was a substantial barrier to implementation in a number of homes.
Discussion and conclusions
The FITS intervention can be delivered at scale and is a robust way of bringing about positive change. The evaluation informed revisions to the person specification for DCCs and DPDCs and factors to enable successful implementation.
Aging and Mental Health 07/2015; In Press. DOI:10.1080/13607863.2015.1063102 · 1.75 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To produce a practice guideline that includes a set of detailed consensus principles regarding the prescription of antipsychotics (APs) amongst people with dementia living in care homes.
We used a modified Delphi consensus procedure with three rounds, where we actively specified and optimized statements throughout the process, utilizing input from four focus groups, carried out in UK, Norway, and the Netherlands. This was done to identify relevant themes and a set of statement that experts agreed upon using the Research and Development/University of California at Los Angeles (RAND/UCLA) methodology.
A total of 72 scientific and clinical experts and 14 consumer experts reached consensus upon 150 statements covering five themes: (1) General prescription stipulations, (2) assessments prior to prescription, (3) care and treatment plan, (4) discontinuation, and (5) long-term treatment.
In this practice guideline, novel information was provided about detailed indication and thresholds of symptoms, risk factors, circumstances at which APs should be stopped or tapered, specific criteria for justifying long-term treatment, involvement of the multidisciplinary team, and family caregiver in the process of prescription. The practice guideline is based on formal consensus of clinicians and consumer experts and provides clinicians relevant practical information that is lacking in current guidelines.
International Psychogeriatrics 06/2015; -1:1-11. DOI:10.1017/S1041610215000745 · 1.93 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Drug repositioning offers an innovative approach to drug discovery with great potential in the field of Alzheimer's Disease and dementia therapeutics. Investigation of licensed compounds enables processing through the drug discovery pipeline in a rapid and cost-effective manner. A growing body of evidence supports the translation of priority compounds to be taken forward to clinical trials, based on established and proposed mechanisms of action. A number of drugs have already entered clinical trial following repositioning, and novel technologies have been created to enable high-throughput screening. This review discusses the novel approaches that build on transcriptional signature profiling to support repositioning in AD, and the novel candidate drugs that are emerging from this exciting new technique.
Frontiers in bioscience (Scholar edition) 06/2015; 7(1):184-188.
[Show abstract][Hide abstract] ABSTRACT: Objectives
Emerging literature suggests that lifestyle factors may play an important role in reducing age-related cognitive decline. There have, however, been few studies investigating the role of cognitively stimulating leisure activities in maintaining cognitive health. This study sought to identify changes in cognitive performance with age and to investigate associations of cognitive performance with several key cognitively stimulating leisure activities. Method
Over 65,000 participants provided demographic and lifestyle information and completed tests of grammatical reasoning, spatial working memory, verbal working memory and episodic memory. ResultsRegression analyses suggested that frequency of engaging in Sudoku or similar puzzles was significantly positively associated with grammatical reasoning, spatial working memory and episodic memory scores. Furthermore, for participants aged under 65years, frequency of playing non-cognitive training computer games was also positively associated with performance in the same cognitive domains. The results also suggest that grammatical reasoning and episodic memory are particularly vulnerable to age-related decline. Further investigation to determine the potential benefits of participating in Sudoku puzzles and non-cognitive computer games is indicated, particularly as they are associated with grammatical reasoning and episodic memory, cognitive domains found to be strongly associated with age-related cognitive decline. Conclusions
Results of this study have implications for developing improved guidance for the public regarding the potential value of cognitively stimulating leisure activities. The results also suggest that grammatical reasoning and episodic memory should be targeted in developing appropriate outcome measures to assess efficacy of future interventions, and in developing cognitive training programmes to prevent or delay cognitive decline. Copyright (c) 2014 John Wiley & Sons, Ltd.
International Journal of Geriatric Psychiatry 04/2015; 30(4). DOI:10.1002/gps.4155 · 2.87 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objective
There is great interest in conducting clinical trials of disease-modifying therapies in the prodromal (early, pre-dementia), asymptomatic stages of Alzheimer's disease. Diagnostic biomarker tests offer a means of identifying prodromal patients, but it is unclear how potential participants feel about their use. Deciding whether to take part in a clinical trial is a complex process in which eligible participants must balance risks and discomforts against uncertain benefits. We sought to explore the views of potential participants through qualitative research methods. Methods
Focus groups with people with early memory problems, current and former family carers explored attitudes towards participating in clinical trials in the prodromal stages of the disease, using an example of anti-amyloid antibody-therapy (immunotherapy), which are currently in development. ResultsDespite the complexities involved, almost all participants had a clear idea about whether they, personally, would like to take part. Many were highly motivated to obtain an unambiguous diagnosis, regardless of their desire to participate in a clinical trial. Participants expressed minimal concern regarding the risk of adverse events associated with immunotherapy, whereas certain tests and trial procedures provoked greater anxiety. People with memory problems were found to assess the study demands in relation to their own priorities and circumstances. Conclusions
The priorities of patients might be different to clinicians and those who design and regulate clinical trials. Patient views can be used to inform the ethical debate around the disclosure of biomarker status, the design of clinical trials and the content of trial information. Copyright (c) 2013 John Wiley & Sons, Ltd.
International Journal of Geriatric Psychiatry 12/2014; 29(1). DOI:10.1002/gps.3958 · 2.87 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Parkinson's disease (PD) affects 10 million people worldwide. Half will develop psychosis, the majority experiencing hallucinations rather than delusions. Emergence of psychosis increases the likelihood of institutionalization and mortality. Where pharmacological treatment is warranted, options are limited. Most currently licensed atypical antipsychotics are ineffective or worsen motor symptoms in people with PD. This review of provides an overview of the current landscape of treatments and the opportunities in emerging research. Clozapine is the only licensed antipsychotic with proven efficacy, although the associated side effects limit its use. With recent advances in understanding the role of serotonin, rational drug design approaches have delivered a novel pharmacological treatment with recently proven efficacy in clinical trials of people with PD and psychosis. Pimavanserin represents an important addition to treatment.
[Show abstract][Hide abstract] ABSTRACT: Introduction:
There is evidence that neurofibrillary tangle (NFT) burden is associated with psychotic symptoms in Alzheimer disease (AD). However, it is not clear whether this association is direct or mediated through the increased cognitive impairment associated with NFTs.
We sought to determine whether the extended MAPT haplotype was associated with the worsening of delusions and hallucinations in a combined cohort of 95 patients who participated in 2 clinical trials of treatment with memantine.
After controlling for baseline dementia severity, exposure to memantine, and antipsychotics, analysis shows that carriers of at least one H2 allele had a 5.4-fold (P = .03) increased risk of worsening hallucinations. There was some evidence of association with worsening delusions but only in analysis by allele.
These results are the first to indicate that the H2 allele of the extended MAPT haplotype negatively affects the course of psychotic symptoms in AD independently of disease severity. It will be important for future research to examine MAPT transcription in people with AD with and without psychotic symptoms to understand the exact mechanisms underlying these findings.
Journal of the American Medical Directors Association 10/2014; 15(12). DOI:10.1016/j.jamda.2014.08.011 · 4.94 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: ABSTRACT Background: The management of disruptive neuropsychiatric symptom (NPS) such as agitation and aggression (A/A) is a major priority in caring for people with Alzheimer's disease (AD). Few effective pharmacological or non-pharmacological options are available. Results of randomized clinical trials (RCTs) of drugs for A/A have been disappointing. This may result from the absence of biological efficacy for medications tested in treating A/A. It may also be related to methodological issues such as the choice of outcomes. The aim of this review was to highlight key methodological issues pertaining to RCTs of current and emerging medications for the treatment of A/A in AD. Methods: We searched PubMed/Medline, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov for RCTs comparing medications with either placebo or other drugs in the treatment of A/A in AD, between January 2008 and December 2013. Results: We identified a total of 18 RCTs; of these, 11 were completed and 7 ongoing. Of the ongoing RCTs, only one is in Phase III. Seven of 10 completed RCTs with reported results did not report greater benefit from drug than placebo. Each of the completed RCTs used a different definition of "clinically significant A/A." There was considerable heterogeneity in study design. The primary endpoints were largely proxy-based but a variety of scales were used. The definition of caregiver and scales used to assess caregiver outcomes were similarly heterogeneous. Placebo response was notable in all trials. Conclusions: This review highlights a great heterogeneity in RCTs design of drugs for A/A in AD and some key methodological issues such as definition of A/A, choice of outcome measures and caregiver participation that could be addressed by an expert consensus to optimize future trials design.
International Psychogeriatrics 09/2014; 27(2):1-17. DOI:10.1017/S1041610214001720 · 1.93 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD) are characterised by the presence of α-synuclein-containing Lewy bodies and Lewy neurites. However, both dementias also show variable degrees of Alzheimer's disease (AD) pathology (senile plaques and neurofibrillary tangles), particularly in areas of the cortex associated with higher cognitive functions. This study investigates the contribution of the individual and combined pathologies in determining the rate of cognitive decline. Cortical α-synuclein, phosphorylated-tau (phosphotau) and Aβ plaque pathology in 34 PDD and 55 DLB patients was assessed semi-quantitatively in four regions of the neocortex. The decline in cognition, assessed by Mini Mental State Examination, correlated positively with the cortical α-synuclein load. Patients also had varying degrees of senile Aβ plaque and phosphotau pathology. Regression analyses pointed to a combined pathology (Aβ plaque plus phosphotau plus α-synuclein positive features), particularly in the prefrontal cortex (BA9) and temporal lobe neocortex with the superior and middle temporal gyrus (BA 21, 22), being a major determining factor in the development of dementia. Thus, cognitive decline in Lewy body dementias is not a consequence of α-synuclein induced neurodegeneration alone but senile plaque and phosphorylated tau pathology also contribute to the overall deficits.