A pharmacy led program to review anti-psychotic prescribing for people with dementia

Background: Anti-psychotics, prescribed to people with dementia, are associated with approximately 1,800 excess annual deaths in the UK. A key public health objective is to limit such prescribing of anti-psychotics. Methods: This project was conducted within primary care in Medway Primary Care Trust (PCT) in the UK. There were 2 stages for the intervention. First, primary care information systems including the dementia register were searched by a pharmacy technician to identify people with dementia prescribed anti-psychotics. Second, a trained specialist pharmacist conducted targeted clinical medication reviews in people with dementia initiated on anti-psychotics by primary care, identified by the data search. Results: Data were collected from 59 practices. One hundred and sixty-one (15.3%) of 1051 people on the dementia register were receiving low-dose anti-psychotics. People with dementia living in residential homes were nearly 3.5 times more likely to receive an anti-psychotic [25.5% of care home residents (118/462) vs. 7.3% of people living at home (43/589)] than people living in their own homes (p?dementia register receiving low-dose anti-psychotics. Of the 161 people with dementia prescribed low-dose anti-psychotics, 91 were receiving on-going treatment from local secondary care mental health services or Learning Disability Teams. Of the remaining 70 patients the anti-psychotic was either withdrawn, or the dosage was reduced, in 43 instances (61.4%) following the pharmacy-led medication review. Conclusions: In total 15.3% of people on the dementia register were receiving a low-dose anti-psychotic. However, such data, including the recent national audit may under-estimate the usage of anti-psychotics in people with dementia. Anti-psychotics were used more commonly within care home settings. The pharmacist-led medication review successfully limited the prescribing of anti-psychotics to people with dementia.

Different molecular pathologies result in similar spatial patterns of cellular inclusions in neurodegenerative disease:a comparative study of eight disorders

Recent research suggests cell-to-cell transfer of pathogenic proteins such as tau and α-synuclein may play a role in neurodegeneration. Pathogenic spread along neural pathways may give rise to specific spatial patterns of the neuronal cytoplasmic inclusions (NCI) characteristic of these disorders. Hence, the spatial patterns of NCI were compared in four tauopathies, viz., Alzheimer's disease, Pick's disease, corticobasal degeneration, and progressive supranuclear palsy, two synucleinopathies, viz., dementia with Lewy bodies and multiple system atrophy, the 'fused in sarcoma' (FUS)-immunoreactive inclusions in neuronal intermediate filament inclusion disease, and the transactive response DNA-binding protein (TDP-43)-immunoreactive inclusions in frontotemporal lobar degeneration, a TDP-43 proteinopathy (FTLD-TDP). Regardless of molecular group or morphology, NCI were most frequently aggregated into clusters, the clusters being regularly distributed parallel to the pia mater. In a significant proportion of regions, the regularly distributed clusters were in the size range 400-800 μm, approximating to the dimension of cell columns associated with the cortico-cortical pathways. The data suggest that cortical NCI in different disorders exhibit a similar spatial pattern in the cortex consistent with pathogenic spread along anatomical pathways. Hence, treatments designed to protect the cortex from neurodegeneration may be applicable across several different disorders. © 2012 Springer-Verlag.

'He was like a zombie':off-label prescription of antipsychotic drugs in dementia

This paper explores the legal position of the off-label prescription of antipsychotic medications to people with dementia who experience behavioural and psychological symptoms of dementia (BPSD). Dementia is a challenging illness, and BPSD can be very difficult for carers to manage, with evidence that this contributes to carer strain and can result in the early institutionalisation of people with dementia. As a result, the prescription of antipsychotic and other neuroleptic medications to treat BPSD has become commonplace, in spite of these drugs being untested and unlicensed for use to treat older people with dementia. In recent years, it has become apparent through clinical trials that antipsychotic drugs increase the risk of cerebrovascular accident (stroke) and death in people with dementia. In addition, these types of medication also have other risk factors for people with dementia, including over-sedation and worsening of cognitive function. Drawing on recent questionnaire (n = 185), focus group (n = 15), and interview (n = 11) data with carers of people with dementia, this paper explores the law relating to off-label prescription, and the applicability of medical negligence law to cases where adverse events follow the use of antipsychotic medication. It is argued that the practice of off-label prescribing requires regulatory intervention in order to protect vulnerable patients. © The Author [2012]. Published by Oxford University Press; all rights reserved.

Laminar distribution of the pathological changes in sporadic frontotemporal lobar degeneration with transactive response (TAR) DNA-binding protein of 43kDa (TDP-43) proteinopathy:a quantitative study using polynomial curve fitting

Aims: Previous data suggest heterogeneity in laminar distribution of the pathology in the molecular disorder frontotemporal lobar degeneration (FTLD) with transactive response (TAR) DNA-binding protein of 43kDa (TDP-43) proteinopathy (FTLD-TDP). To study this heterogeneity, we quantified the changes in density across the cortical laminae of neuronal cytoplasmic inclusions, glial inclusions, neuronal intranuclear inclusions, dystrophic neurites, surviving neurones, abnormally enlarged neurones, and vacuoles in regions of the frontal and temporal lobe. Methods: Changes in density of histological features across cortical gyri were studied in 10 sporadic cases of FTLD-TDP using quantitative methods and polynomial curve fitting. Results: Our data suggest that laminar neuropathology in sporadic FTLD-TDP is highly variable. Most commonly, neuronal cytoplasmic inclusions, dystrophic neurites and vacuolation were abundant in the upper laminae and glial inclusions, neuronal intranuclear inclusions, abnormally enlarged neurones, and glial cell nuclei in the lower laminae. TDP-43-immunoreactive inclusions affected more of the cortical profile in longer duration cases; their distribution varied with disease subtype, but was unrelated to Braak tangle score. Different TDP-43-immunoreactive inclusions were not spatially correlated. Conclusions: Laminar distribution of pathological features in 10 sporadic cases of FTLD-TDP is heterogeneous and may be accounted for, in part, by disease subtype and disease duration. In addition, the feedforward and feedback cortico-cortical connections may be compromised in FTLD-TDP. © 2012 The Authors. Neuropathology and Applied Neurobiology © 2012 British Neuropathological Society.

Medication -related adverse events in older people with dementia:causes and possible solutions

This submission for a PhD by previously published work is based upon six publications in peer reviewed journals, reflecting a 9-year research programme. My research has shown, in a coherent and original way, the difficulty in treating people with dementia with safe and effective medication whilst providing research-founded guidance to develop mechanisms to optimise medication choice and minimise iatrogenic events. A wide range of methods, including systematic reviews, meta-analysis, randomised controlled trials (RCTs), quantitative research and mixed methods were used to generate the data, which supported the exploration of three themes. The first theme, to understand the incidence and causes of medication errors in dementia services, identified that people with dementia may be more susceptible to medication-related iatrogenic disease partly due to inherent disease-related characteristics. One particular area of concern is the use of anti-psychotics to treat the Behavioural and Psychological Symptoms of Dementia (BPSD). The second and third themes, respectively, investigated a novel pharmacological and health services intervention to limit anti-psychotic usage. The second phase found that whilst the glutamate receptor blocker memantine showed some promise, further research was clearly required. The third phase found that anti-psychotic usage in dementia may be higher than official figures suggest and that medication review linking primary and secondary care can limit such usage. My work has been widely cited, reflecting a substantial contribution to the field, in terms of our understanding of the causes of, and possible solutions to limit, medication-related adverse events in people with dementia. More importantly, this work has already informed clinical practice, patients, carers and policy makers by its demonstrable impact on health policy. In particular my research has identified key lines of enquiry for future work and for the development of my own personal research programme to reduce the risk associated with medication in this vulnerable population.

Spatial patterns of phosphorylation-dependent TDP-43-immunoreactive neuronal cytoplasmic inclusions (NCI) in frontotemporal lobar degeneration with TDP-43 proteinopathy (FTLD-TDP)

The transactive response (TAR) DNA-binding protein of 43kDa (TDP-43) is an RNA binding protein encoded by the TARDPB gene. Abnormal aggregations of TDP-43 in neurons in the form of neuronal cytoplasmic inclusions (NCI) are the pathological hallmark of frontotemporal lobar degeneration with TDP-43 proteinopathy (FTLD-TDP). To investigate the role of TDP-43 in FTLD-TDP, the spatial patterns of the NCI were studied in frontal and temporal cortex of FTLD-TDP cases using a phosphorylation dependent anti-TDP-43 antibody (pTDP-43). In many regions, the NCI formed clusters and the clusters were distributed regularly parallel to the tissue boundary. In about 35% of cortical regions, cluster size of the NCI was within the size range of the modular columns of the cortex. The spatial patterns of the pTDP-immunoreactive inclusions were similar to those revealed by a phosphorylation-independent anti-TDP-43 antibody and also similar to inclusions characterized by other molecular pathologies such as tau, ?-synuclein and ‘fused in sarcoma’ (FUS). In conclusion, the data suggest degeneration of cortical and hippocampal anatomical pathways associated with accumulation of cellular pTDP-43 is characteristic of FTLD-TDP. In addition, the data are consistent with the hypothesis of cell to cell transfer of pTDP-43 within the brain.

A quantitative study of α-synuclein pathology in fifteen cases of dementia associated with Parkinson disease

The α-synuclein-immunoreactive pathology of dementia associated with Parkinson disease (DPD) comprises Lewy bodies (LB), Lewy neurites (LN), and Lewy grains (LG). The densities of LB, LN, LG together with vacuoles, neurons, abnormally enlarged neurons (EN), and glial cell nuclei were measured in fifteen cases of DPD. Densities of LN and LG were up to 19 and 70 times those of LB, respectively, depending on region. Densities were significantly greater in amygdala, entorhinal cortex (EC), and sectors CA2/CA3 of the hippocampus, whereas middle frontal gyrus, sector CA1, and dentate gyrus were least affected. Low densities of vacuoles and EN were recorded in most regions. There were differences in the numerical density of neurons between regions, but no statistical difference between patients and controls. In the cortex, the density of LB and vacuoles was similar in upper and lower laminae, while the densities of LN and LG were greater in upper cortex. The densities of LB, LN, and LG were positively correlated. Principal components analysis suggested that DPD cases were heterogeneous with pathology primarily affecting either hippocampus or cortex. The data suggest in DPD: (1) ratio of LN and LG to LB varies between regions, (2) low densities of vacuoles and EN are present in most brain regions, (3) degeneration occurs across cortical laminae, upper laminae being particularly affected, (4) LB, LN and LG may represent degeneration of the same neurons, and (5) disease heterogeneity may result from variation in anatomical pathway affected by cell-to-cell transfer of α-synuclein. © 2013 Springer-Verlag Wien.

Optimising primary care for people with dementia

This review considers key areas in primary care regarding the diagnosis of dementia. Issues surrounding assessment, policy and incentives are considered. In addition, the relevance of non-medication approaches for dementia in primary care, which aim to enhance or maintain quality of life by maximising psychological and social function in the context of existing disabilities, is deliberated. Finally, key issues about primary care medication management are considered, and relevant therapeutic strategies with recommendation for a collaborative approach that improve outcomes by linking primary and secondary healthcare services - including general practice and pharmacy - with social care needs are weighed up. A key aspect of such a collaborative approach is to support informal carers in optimising medication.

A review of studies describing the use of acetyl cholinesterase inhibitors in Parkinson's disease dementia

Objective:  To review the literature relating to the use of acetyl cholinesterase inhibitors in Parkinson's disease dementia (PDD). Method:  MEDLINE (1966 – December 2004), PsychINFO (1972 – December 2004), EMBASE (1980 – December 2004), CINHAL (1982 – December 2004), and the Cochrane Collaboration were searched in December 2004. Results:  Three controlled trials and seven open studies were identified. Efficacy was assessed in three key domains: cognitive, neuropsychiatric and parkinsonian symptoms. Conclusion:  Cholinesterase inhibitors have a moderate effect against cognitive symptoms. There is no clear evidence of a noticeable clinical effect against neuropsychiatric symptoms. Tolerability including exacerbation of motor symptoms – in particular tremor – may limit the utility of cholinesterase inhibitors.

Cholinesterase inhibitors for Parkinson's disease dementia

Background - The loss of cholinergic, dopaminergic and noradrenergic innervations seen in Parkinson's Disease Dementia (PDD) suggest a potential role for cholinesterase inhibitors. Concerns have been expressed about a theoretical worsening of Parkinson's disease related symptoms, particularly movement symptoms. Objectives - To assess the efficacy, safety, tolerability and health economic data relating to the use of cholinesterase inhibitors in PDD. Search methods - The trials were identified from the Specialized Register of the Cochrane Dementia and Cognitive Improvement Group on 19 April 2005 using the search term parkinson*. This register contains records from major health care databases and many ongoing trial databases and is updated regularly. Comprehensive searches of abstracts from major scientific meetings were performed. Pharmaceutical companies were approached for information regarding additional and ongoing studies. Selection criteria - Randomized, double-blind, placebo-controlled studies assessing the effectiveness of cholinesterase inhibitors in PDD. Inclusion and exclusion criteria were stated to limit bias. Data collection and analysis - Two reviewers (IM, CF) independently reviewed the quality of the studies utilizing criteria from the Cochrane Collaboration Handbook. Medications were examined separately and as a group. The outcome measures assessed were in the following domains: neuropsychiatric features, cognition, global impression, daily living activities, quality of life, burden on caregiver, Parkinsonian related symptoms, treatment acceptability as determined by withdrawal from trials, safety as determined by the frequency of adverse events, institutionalisation, death and health economic factors. Main results - A detailed and systematic search of relevant databases identified one published randomized, double-blind, placebo-controlled study (Emre 2004) involving 541 patients that compared rivastigmine with placebo. Rivastigmine produced statistically significant improvements in several outcome measures. On the primary cognitive measure, the ADAS-Cog, rivastigmine was associated with a 2.80 point ADAS-Cog improvement [WMD -2.80, 95% Cl -4.26 to -1.34, P = 0.0002] and a 2.50 point ADCS-ADL improvement [95% Cl 0.43 to 4.57, P = 0.02] relative to placebo. Clinically meaningful (moderate or marked) improvement occurred in 5.3% more patients on rivastigmine, and meaningful worsening occurred in 10.1% more patients on placebo. Tolerability appeared to be a significant issue. Significantly more patients on rivastigmine dropped out of the study due to adverse events [62/362 versus 14/179, OR 2.44, 95% Cl 1.32 to 4.48, P = 0.004]. Nausea [20/179 versus 105/362, OR 3.25, 95% Cl 1.94 to 5.45, P < 0.00001], tremor [7/179 versus 37/362, OR 2.80, 95% Cl 1.22 to 6.41, P = 0.01] and in particular vomiting [3/179 versus 60/362, OR 11.66, 95% Cl 3.60 to 37.72, P < 0.0001] were significantly more common with rivastigmine. However, significantly fewer patients died on rivastigmine than placebo [4/362 versus 7/179, OR 0.27, 95% CI 0.08 to 0.95, P = 0.04] Authors' conclusions - Rivastigmine appears to improve cognition and activities of daily living in patients with PDD. This results in clinically meaningful benefit in about 15% of cases. There is a need for more studies utilising pragmatic measures such as time to residential care facility and both patient and carer quality of life assessments. Future trials should involve other cholinesterase inhibitors, utilise tools to analyse the data that limit any bias and measure health economic factors. It is unlikely that relying solely on the last observation carried forward (LOCF) is sufficient. Publication of the observed case data in the largest trial would assist (Emre 2004). Adverse events were associated with the cholinergic activity of rivastigmine, but may limit patient acceptability as evidenced by the high drop out rate in the active arm.

Systematic review investigating the reporting of comorbidities and medication in randomized controlled trials of people with dementia

Objectives: dementia is a debilitating condition characterised by global loss of cognitive and intellectual functioning, which reduces social and occupational performance. This population frequently presents with medical co-morbidities such as hypertension, cardiovascular disease and diabetes. The CONSORT statement outlines recommended guidance on reporting of participant characteristics in clinical trials. It is, however, unclear how much these are adhered to in trials assessing people with dementia. This paper assesses the reporting of medical co-morbidities and prescribed medications for people with dementia within randomised controlled trial (RCT) reports. Design: a systematic review of the published literature from the databases AMED, CINAHL, MEDLINE, EMBASE and the Cochrane Clinical Trial Registry from 1 January 1997 to 9 January 2014 was undertaken in order to identify RCTs detailing baseline medical co-morbidities and prescribed medications . Eligible studies were appraised using the Critical Appraisal Skills Programme (CASP) RCT appraisal tool, and descriptive statistical analyses were calculated to determine point prevalence. Results: nine trials, including 1474 people with dementia, were identified presenting medical co-morbidity data. These indicated neurological disorders ( prevalence 91%), vascular disorders (prevalence 91%), cardiac disorders ( prevalence 74%) and ischaemic cerebrovascular disease ( prevalence 53%) were most frequently seen. Conclusions: published RCTs poorly report medical co-morbidities and medications for people with dementia. Future trials should include the report of these items to allow interpretation of whether the results are generalisable to frailer older populations.

The importance of detecting and managing comorbidities in people with dementia?

Dementia is a debilitating condition characterised by global loss of cognitive and intellectual functioning, which gradually interferes with social and occupational performance. It is a common worldwide condition with a significant impact on society. There are currently 36 million people worldwide with Alzheimer's disease (AD) and other dementias [1]. This is expected to more than double by 2030 (65 million) and reach ∼115 million in 2050, unless a major breakthrough is made. The worldwide societal costs were estimated at USD 604 billion in 2010 and rising [2]. To date research on the specific physical healthcare needs of people with dementia has been neglected. Yet, physical comorbidities are reported as common in people with dementia [3] and have been shown to lead to increased disability and reduced quality of life for the affected person and their carer [4]. Dementia is most frequently associated with older people who often present with other medical conditions, known as co-morbidities. Such co-morbidities include diabetes, chronic obstructive pulmonary disorder, musculoskeletal disorders and chronic cardiac failure and are common, 61% of people with …

Perspectives of carers on medication management in dementia:lessons from collaboratively developing a research proposal

Background: The need for carers to manage medication-related problems for people with dementia living in the community raises dilemmas, which can be identified by carers and people with dementia as key issues for developing carer-relevant research projects.A research planning Public Patient Involvement (PPI) workshop using adapted focus group methodology was held at the Alzheimer's Society's national office, involving carers of people with dementia who were current members of the Alzheimer's Society Research Network (ASRN) in dialogue with health professionals aimed to identify key issues in relation to medication management in dementia from the carer viewpoint. The group was facilitated by a specialist mental health pharmacist, using a topic guide developed systematically with carers, health professionals and researchers. Audio-recordings and field notes were made at the time and were transcribed and analysed thematically. The participants included nine carers in addition to academics, clinicians, and staff from DeNDRoN (Dementias and Neurodegenerative Diseases Research Network) and the Alzheimer's Society. Findings. Significant themes, for carers, which emerged from the workshop were related to: (1) medication usage and administration practicalities, (2) communication barriers and facilitators, (3) bearing and sharing responsibility and (4) weighing up medication risks and benefits. These can form the basis for more in-depth qualitative research involving a broader, more diverse sample. Discussion. The supported discussion enabled carer voices and perspectives to be expressed and to be linked to the process of identifying problems in medications management as directly experienced by carers. This was used to inform an agenda for research proposals which would be meaningful for carers and people with dementia. © 2014 Poland et al.; licensee BioMed Central Ltd.

From the medicalisation of dementia to the politics of memory and identity in three Spanish documentary films:Bicicleta, cullera, poma, Las voces de la memoria and Bucarest: la memòria perduda

This paper explores how the concept of Alzheimer’s disease (AD) is constructed through Spanish media and documentary films and how it is represented. The article analyses three documentary films and the cultural and social contexts in and from which they emerged: Solé´s Bucarest: la memòria perduda [Bucharest: Memory Lost] (2007), Bosch´s Bicicleta, cullera, poma [Bicycle, Spoon, Apple] (2010) , and Frabra’s Las voces de la memoria [Memory´s Voices] (2011). The three documentary films approach AD from different perspectives, creating well-structured discourses of what AD represents for contemporary Spanish society, from medicalisation of AD to issues of personhood and citizenship. These three films are studied from an interdisciplinary perspective, in an effort to strengthen the links between ageing and dementia studies and cultural studies. Examining documentary film representations of AD from these perspectives enables semiotic analyses beyond the aesthetic perspectives of film studies, and the exploration of the articulation of knowledge and power in discourses about AD in contemporary Spain