The prognosis of dementia with Lewy bodies Mueller, Christoph, Dr; Ballard, Clive, Prof; Corbett, Anne, PhD ...
Lancet neurology,
05/2017, Letnik:
16, Številka:
5
Journal Article
Recenzirano
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Summary Dementia with Lewy bodies is the second most common form of neurodegenerative dementia, yet scarce evidence is available about its prognosis and natural history, which are crucial to inform ...clinical practice and research. Patients with dementia with Lewy bodies might have a less favourable prognosis, with accelerated cognitive decline, shorter lifespan, and increased admission to residential care than patients with Alzheimer's disease. Health-care costs and, importantly, caregiver burden, are also reported to be higher in dementia with Lewy bodies than in Alzheimer's disease. It is probable that causative factors for this less favourable prognosis are the increased prevalence and early emergence of neuropsychiatric symptoms in patients with dementia with Lewy bodies, and the challenge of accurate diagnosis. Evidence concerning quality of life and hospital admission rates is limited, despite their clinical and economic relevance.
Summary Down's syndrome is the most common genetic cause of learning difficulties, and individuals with this condition represent the largest group of people with dementia under the age of 50 years. ...Genetic drivers result in a high frequency of Alzheimer's pathology in these individuals, evident from neuroimaging, biomarker, and neuropathological findings, and a high incidence of cognitive decline and dementia. However, cognitive assessment is challenging, and diagnostic methods have not been fully validated for use in these patients; hence, early diagnosis remains difficult. Evidence regarding the benefits of cholinesterase inhibitors and other therapeutic options to treat or delay progressive cognitive decline or dementia is very scarce. Despite close similarities with late-onset Alzheimer's disease, individuals with Down's syndrome respond differently to treatment, and a targeted approach to drug development is thus necessary. Genetic and preclinical studies offer opportunities for treatment development, and potential therapies have been identified using these approaches.
Drug repositioning and repurposing can enhance traditional drug development efforts and could accelerate the identification of new treatments for individuals with Alzheimer disease (AD) dementia and ...mild cognitive impairment. Transcriptional profiling offers a new and highly efficient approach to the identification of novel candidates for repositioning and repurposing. In the future, novel AD transcriptional signatures from cells isolated at early stages of disease, or from human neurons or microglia that carry mutations that increase the risk of AD, might be used as probes to identify additional candidate drugs. Phase II trials assessing repurposed agents must consider the best target population for a specific candidate therapy as well as the mechanism of action of the treatment. In this Review, we highlight promising compounds to prioritize for clinical trials in individuals with AD, and discuss the value of Delphi consensus methodology and evidence-based reviews to inform this prioritization process. We also describe emerging work, focusing on the potential value of transcript signatures as a cost-effective approach to the identification of novel candidates for repositioning.
Summary Background Parkinson's disease psychosis, which includes hallucinations and delusions, is frequent and debilitating in people with Parkinson's disease. We aimed to assess safety and efficacy ...of pimavanserin, a selective serotonin 5-HT2A inverse agonist, in this population. Methods In our 6 week, randomised, double-blind, placebo-controlled study, we enrolled adults (aged ≥40 years) with Parkinson's disease psychosis. Antipsychotic treatments were not permitted during the study, but controlled antiparkinsonian medication or deep brain stimulation was allowed. Eligible participants entered a 2 week non-pharmacological lead-in phase to limit the placebo response, after which they were randomly allocated (1:1) to receive pimavanserin 40 mg per day or matched placebo. The primary outcome was antipsychotic benefit as assessed by central, independent raters with the Parkinson's disease-adapted scale for assessment of positive symptoms (SAPS-PD) in all patients who received at least one dose of study drug and had a SAPS assessment at baseline and at least one follow-up. We assessed safety and tolerability in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov , number NCT01174004. Findings Between Aug 11, 2010, and Aug 29, 2012, we randomly allocated 199 patients to treatment groups. For 90 recipients of placebo and 95 recipients of pimavanserin included in the primary analysis, pimavanserin was associated with a −5·79 decrease in SAPS-PD scores compared with −2·73 for placebo (difference −3·06, 95% CI −4·91 to −1·20; p=0·001; Cohen's d 0·50). Ten patients in the pimavanserin group discontinued because of an adverse event (four due to psychotic disorder or hallucination within 10 days of start of the study drug) compared with two in the placebo group. Overall, pimavanserin was well tolerated with no significant safety concerns or worsening of motor function. Interpretation Pimavanserin may benefit patients with Parkinson's disease psychosis for whom few other treatment options exist. The trial design used in this study to manage placebo response could have applicability to other studies in neuropsychiatric disease. Funding ACADIA Pharmaceuticals.
Agitation is a common, challenging symptom affecting large numbers of people with dementia and impacting on quality of life (QoL). There is an urgent need for evidence-based, cost-effective ...psychosocial interventions to improve these outcomes, particularly in the absence of safe, effective pharmacological therapies. This study aimed to evaluate the efficacy of a person-centred care and psychosocial intervention incorporating an antipsychotic review, WHELD, on QoL, agitation, and antipsychotic use in people with dementia living in nursing homes, and to determine its cost.
This was a randomised controlled cluster trial conducted between 1 January 2013 and 30 September 2015 that compared the WHELD intervention with treatment as usual (TAU) in people with dementia living in 69 UK nursing homes, using an intention to treat analysis. All nursing homes allocated to the intervention received staff training in person-centred care and social interaction and education regarding antipsychotic medications (antipsychotic review), followed by ongoing delivery through a care staff champion model. The primary outcome measure was QoL (DEMQOL-Proxy). Secondary outcomes were agitation (Cohen-Mansfield Agitation Inventory CMAI), neuropsychiatric symptoms (Neuropsychiatric Inventory-Nursing Home Version NPI-NH), antipsychotic use, global deterioration (Clinical Dementia Rating), mood (Cornell Scale for Depression in Dementia), unmet needs (Camberwell Assessment of Need for the Elderly), mortality, quality of interactions (Quality of Interactions Scale QUIS), pain (Abbey Pain Scale), and cost. Costs were calculated using cost function figures compared with usual costs. In all, 847 people were randomised to WHELD or TAU, of whom 553 completed the 9-month randomised controlled trial. The intervention conferred a statistically significant improvement in QoL (DEMQOL-Proxy Z score 2.82, p = 0.0042; mean difference 2.54, SEM 0.88; 95% CI 0.81, 4.28; Cohen's D effect size 0.24). There were also statistically significant benefits in agitation (CMAI Z score 2.68, p = 0.0076; mean difference 4.27, SEM 1.59; 95% CI -7.39, -1.15; Cohen's D 0.23) and overall neuropsychiatric symptoms (NPI-NH Z score 3.52, p < 0.001; mean difference 4.55, SEM 1.28; 95% CI -7.07,-2.02; Cohen's D 0.30). Benefits were greatest in people with moderately severe dementia. There was a statistically significant benefit in positive care interactions as measured by QUIS (19.7% increase, SEM 8.94; 95% CI 2.12, 37.16, p = 0.03; Cohen's D 0.55). There were no statistically significant differences between WHELD and TAU for the other outcomes. A sensitivity analysis using a pre-specified imputation model confirmed statistically significant benefits in DEMQOL-Proxy, CMAI, and NPI-NH outcomes with the WHELD intervention. Antipsychotic drug use was at a low stable level in both treatment groups, and the intervention did not reduce use. The WHELD intervention reduced cost compared to TAU, and the benefits achieved were therefore associated with a cost saving. The main limitation was that antipsychotic review was based on augmenting processes within care homes to trigger medical review and did not in this study involve proactive primary care education. An additional limitation was the inherent challenge of assessing QoL in this patient group.
These findings suggest that the WHELD intervention confers benefits in terms of QoL, agitation, and neuropsychiatric symptoms, albeit with relatively small effect sizes, as well as cost saving in a model that can readily be implemented in nursing homes. Future work should consider how to facilitate sustainability of the intervention in this setting.
ISRCTN Registry ISRCTN62237498.
Cognitive training (CT) offers a potential approach for dementia prevention and maintenance of cognitive function in older adults. Online delivery provides a cost-effective means of implementing CT ...compared with in-person interventions, with the potential of providing an effective public health intervention for risk reduction.
A double-blind 6-month online randomized controlled trial in adults older than 50 randomized to General CT, Reasoning CT, or control. The primary outcome was instrumental activities of daily living (IADL) in adults older than 60. Secondary outcomes were reasoning, verbal short-term memory, spatial working memory, verbal learning (VL), and digit vigilance in adults older than 50. Secondary analyses were performed with a group defined as showing age-associated impairment in reasoning according to baseline scores in this domain.
A total of 2912 adults older than 60 (6742 > 50) participated. General and reasoning packages conferred benefit to IADL (P = .008, P = .011), reasoning (P < 0.0001, P < .0001), and VL (P = .007, P = .008) at 6 months. Benefit in reasoning was evident from 6 weeks. Other benefits developed over 6 months. Analysis of participants with age-associated impairment also showed the same pattern of benefit. A clear dose-response effect was seen.
Online CT confers significant benefit to cognition and function in older adults, with benefit favoring the Reasoning package. Scale of benefit is comparable with in-person training, indicating its potential as a public health intervention. Impact on the group with age-associated impairment indicates a particular sensitivity to this at-risk group, which merits further investigation.
The study determined the one year incidence of post operative cognitive decline (POCD) and evaluated the effectiveness of an intra-operative anaesthetic intervention in reducing post-operative ...cognitive impairment in older adults (over 60 years of age) undergoing elective orthopaedic or abdominal surgery.
The design was a prospective cohort study with a nested randomised, controlled intervention trial, using intra-operative BiSpectral index and cerebral oxygen saturation monitoring to enable optimisation of anaesthesia depth and cerebral oxygen saturation in older adults undergoing surgery.
In the 52 week prospective cohort study (192 surgical patients and 138 controls), mild (χ(2) = 17.9 p<0.0001), moderate (χ(2) = 7.8 p = 0.005) and severe (χ(2) = 5.1 p = 0.02) POCD were all significantly higher after 52 weeks in the surgical patients than among the age matched controls. In the nested RCT, 81 patients were randomized, 73 contributing to the data analysis (34 intervention, 39 control). In the intervention group mild POCD was significantly reduced at 1, 12 and 52 weeks (Fisher's Exact Test p = 0.018, χ(2) = 5.1 p = 0.02 and χ(2) = 5.9 p = 0.015), and moderate POCD was reduced at 1 and 52 weeks (χ(2) = 4.4 p = 0·037 and χ(2) = 5.4 p = 0.02). In addition there was significant improvement in reaction time at all time-points (Vigilance Reaction Time MWU Z = -2.1 p = 0.03, MWU Z = -2.7 p = 0.004, MWU Z = -3.0 p = 0.005), in MMSE at one and 52 weeks (MWU Z = -2.9 p = 0.003, MWU Z = -3.3 p = 0.001), and in executive function at 12 and 52 weeks (Trail Making MWU Z = -2.4 p = .0.018, MWU Z = -2.4 p = 0.019).
POCD is common and persistent in older adults following surgery. The results of the nested RCT indicate the potential benefits of intra-operative monitoring of anaesthetic depth and cerebral oxygenation as a pragmatic intervention to reduce post-operative cognitive impairment.
Controlled-Trials.com ISRCTN39503939.
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