Abstract
Given considerable variation in diagnostic and therapeutic practice, there is a need for national guidance on the use of neuroimaging, fluid biomarkers, cognitive testing, follow-up and ...diagnostic terminology in mild cognitive impairment (MCI). MCI is a heterogenous clinical syndrome reflecting a change in cognitive function and deficits on neuropsychological testing but relatively intact activities of daily living. MCI is a risk state for further cognitive and functional decline with 5–15% of people developing dementia per year. However, ~50% remain stable at 5 years and in a minority, symptoms resolve over time. There is considerable debate about whether MCI is a useful clinical diagnosis, or whether the use of the term prevents proper inquiry (by history, examination and investigations) into underlying causes of cognitive symptoms, which can include prodromal neurodegenerative disease, other physical or psychiatric illness, or combinations thereof. Cognitive testing, neuroimaging and fluid biomarkers can improve the sensitivity and specificity of aetiological diagnosis, with growing evidence that these may also help guide prognosis. Diagnostic criteria allow for a diagnosis of Alzheimer’s disease to be made where MCI is accompanied by appropriate biomarker changes, but in practice, such biomarkers are not available in routine clinical practice in the UK. This would change if disease-modifying therapies became available and required a definitive diagnosis but would present major challenges to the National Health Service and similar health systems. Significantly increased investment would be required in training, infrastructure and provision of fluid biomarkers and neuroimaging. Statistical techniques combining markers may provide greater sensitivity and specificity than any single disease marker but their practical usefulness will depend on large-scale studies to ensure ecological validity and that multiple measures, e.g. both cognitive tests and biomarkers, are widely available for clinical use. To perform such large studies, we must increase research participation amongst those with MCI.
The global impact of Alzheimer's disease (AD) continues to increase, and focused efforts are needed to address this immense public health challenge. National leaders have set a goal to prevent or ...effectively treat AD by 2025. In this paper, we discuss the path to 2025, and what is feasible in this time frame given the realities and challenges of AD drug development, with a focus on disease-modifying therapies (DMTs). Under the current conditions, only drugs currently in late Phase 1 or later will have a chance of being approved by 2025. If pipeline attrition rates remain high, only a few compounds at best will meet this time frame. There is an opportunity to reduce the time and risk of AD drug development through an improvement in trial design; better trial infrastructure; disease registries of well-characterized participant cohorts to help with more rapid enrollment of appropriate study populations; validated biomarkers to better detect disease, determine risk and monitor disease progression as well as predict disease response; more sensitive clinical assessment tools; and faster regulatory review. To implement change requires efforts to build awareness, educate and foster engagement; increase funding for both basic and clinical research; reduce fragmented environments and systems; increase learning from successes and failures; promote data standardization and increase wider data sharing; understand AD at the basic biology level; and rapidly translate new knowledge into clinical development. Improved mechanistic understanding of disease onset and progression is central to more efficient AD drug development and will lead to improved therapeutic approaches and targets. The opportunity for more than a few new therapies by 2025 is small. Accelerating research and clinical development efforts and bringing DMTs to market sooner would have a significant impact on the future societal burden of AD. As these steps are put in place and plans come to fruition, e.g., approval of a DMT, it can be predicted that momentum will build, the process will be self-sustaining, and the path to 2025, and beyond, becomes clearer.
Summary Background Immunisation of patients with Alzheimer's disease with full-length amyloid-β peptide (Aβ42 ) can clear amyloid plaques from the brain. Our aim was to assess the relation between ...Aβ42 immune response, degree of plaque removal, and long-term clinical outcomes. Methods In June, 2003, consent for long-term clinical follow-up, post-mortem neuropathological examination, or both, was sought from 80 patients (or their carers) who had entered a phase I randomised, placebo-controlled trial of immunisation with Aβ42 (AN1792, Elan Pharmaceuticals) in September, 2000. The follow-up study was completed in September, 2006. Plaques were assessed in terms of the percentage area of the cortex with Aβ immunostaining (Aβ load) and in terms of characteristic histological features reflecting plaque removal. Survival of all 80 individuals until severe dementia or death was assessed with a Cox proportional hazard model. Findings 20 participants—15 in the AN1792 group, five in the placebo group—died before follow-up started. A further 22 patients—19 in the AN1792 group, three in the placebo group—died during follow-up. Nine of the deceased patients, all in the AN1792 group, had given consent for post-mortem analysis; one of these who did not die with Alzheimer's disease was excluded. In the remaining eight participants who received immunisation and who were examined neuropathologically, mean Aβ load was lower than in an unimmunised control group that was matched for age at death (2·1% SE 0·7 in treated participants vs 5·1% 0·9 in controls; mean difference 3·0%, 95% CI 0·6–5·4; p=0·02). Although there was considerable variation in Aβ load and degree of plaque removal among immunised participants, the degree of plaque removal varied significantly with mean antibody response attained during the treatment study period (Kruskal-Wallis p=0·02). Seven of the eight immunised patients who underwent post-mortem assessment, including those with virtually complete plaque removal, had severe end stage dementia before death. In the whole cohort, there was no evidence of improved survival (hazard ratio 0·93, 95% CI 0·43–3·11; p=0·86) or of an improvement in the time to severe dementia (1·18, 0·45–3·11; p=0·73) in the AN1792 group versus the placebo group. Interpretation Although immunisation with Aβ42 resulted in clearance of amyloid plaques in patients with Alzheimer's disease, this clearance did not prevent progressive neurodegeneration. Funding Alzheimer's Research Trust, Medical Research Council.
Basic research advances in recent years have furthered our understanding of the natural history of Alzheimer's disease (AD). It is now recognized that pathophysiological changes begin many years ...prior to clinical manifestations of disease and the spectrum of AD spans from clinically asymptomatic to severely impaired. Defining AD purely by its clinical presentation is thus artificial and efforts have been made to recognize the disease based on both clinical and biomarker findings. Advances with biomarkers have also prompted a shift in how the disease is considered as a clinico-pathophysiological entity, with an increasing appreciation that AD should not only be viewed with discrete and defined clinical stages, but as a multifaceted process moving along a seamless continuum. Acknowledging this concept is critical to understanding the development process for disease-modifying therapies, and for initiating effective diagnostic and disease management options. In this article, we discuss the concept of a disease continuum from pathophysiological, biomarker, and clinical perspectives, and highlight the importance of considering AD as a continuum rather than discrete stages. While the pathophysiology of AD has still not been elucidated completely, there is ample evidence to support researchers and clinicians embracing the view of a disease continuum in their study, diagnosis, and management of the disease.
In his Philosophical Investigations, Wittgenstein famously noted that the formation of semantic representations requires more than a simple combination of verbal and nonverbal features to generate ...conceptually based similarities and differences. Classical and contemporary neuroscience has tended to focus upon how different neocortical regions contribute to conceptualization through the summation of modality-specific information. The additional yet critical step of computing coherent concepts has received little attention. Some computational models of semantic memory are able to generate such concepts by the addition of modality-invariant information coded in a multidimensional semantic space. By studying patients with semantic dementia, we demonstrate that this aspect of semantic memory becomes compromised following atrophy of the anterior temporal lobes and, as a result, the patients become increasingly influenced by superficial rather than conceptual similarities.
There is a major need for longitudinal research examining the experiences of people with dementia and their primary carers, as relatively little is known about how the factors associated with ...capability to 'live well' vary over time. The main aim of the IDEAL-2 study is to investigate how and why, over time, people with dementia and their primary carers might vary in their capability to live well with dementia, whilst exploring both their use of health and care services and their unmet needs.
IDEAL-2 will build on the Improving the experience of Dementia and Enhancing Active Life (IDEAL) cohort of 1547 people (who, at recruitment between July 2014 and July 2016, had mild-to-moderate dementia), and their 1283 primary carers in Great Britain. The existing cohort will be enriched with additional participants with mild-to-moderate dementia (and their primary carers where available and willing) from the following groups: people with rarer forms of dementia, and/or those who are ≥90 years or < 65 years of age at time of recruitment. We will assess the primary outcome, capability to live well with dementia, and the factors influencing it using questionnaires at yearly intervals for 3 years. Additionally, we will seek to link the cohort data with administrative data to obtain information about health service use. Some participants will be invited for in-depth face-to-face interviews. The cohort study will be supplemented by linked research focusing on: the co-production of new measures of living well; including the perspectives of people with advanced dementia living in residential care settings; including people with dementia from black, Asian, and minority ethnic groups; and understanding the experience of people living with undiagnosed dementia.
IDEAL-2 will provide evidence about the key indicators of, and factors associated with, living well over the course of dementia and how these differ for particular subgroups. It will tell us which combinations of services and support are most beneficial and cost-effective. Moreover, the IDEAL-2 study will gather evidence from under-researched groups of people with dementia, who are likely to have their own distinct perceptions of living well.
Cognitive rehabilitation (CR) is an individualised, person-centred intervention for people with mild to moderate dementia that addresses the impact of cognitive impairment on everyday functioning.
To ...determine whether or not CR is a clinically effective and cost-effective intervention for people with mild to moderate Alzheimer's disease or vascular or mixed dementia, and their carers.
This multicentre randomised controlled trial compared CR with treatment as usual (TAU). Following a baseline assessment and goal-setting to identify areas of everyday functioning that could be improved or better managed, participants were randomised (1 : 1) via secure web access to an independent randomisation centre to receive either TAU or CR and followed up at 3 and 9 months post randomisation.
Community.
Participants had an
, Tenth Edition, diagnosis of Alzheimer's disease or vascular or mixed dementia, had mild to moderate cognitive impairment (Mini Mental State Examination score of ≥ 18 points), were stable on medication if prescribed, and had a family carer who was willing to contribute. The exclusion criteria were people with a history of brain injury or other neurological disorder and an inability to speak English. To achieve adequate power, we needed 350 people to complete the trial, with 175 people in each trial arm.
Cognitive rehabilitation consisted of 10 therapy sessions over 3 months, followed by four maintenance sessions over 6 months, delivered in participants' homes. The therapists were nine occupational therapists and one nurse.
The primary outcome was self-reported goal attainment at 3 months. Goal attainment was also assessed at 9 months. Carers provided independent ratings of goal attainment at both time points. The secondary outcomes were participant quality of life, mood, self-efficacy and cognition, and carer stress, health status and quality of life. The assessments at 3 and 9 months were conducted by researchers who were blind to the participants' group allocation.
A total of 475 participants were randomised (CR arm,
= 239; TAU arm,
= 236), 427 participants (90%) completed the trial and 426 participants were analysed (CR arm,
= 208, TAU arm,
= 218). At 3 months, there were statistically significant large positive effects for participant-rated goal attainment mean change in the CR arm: 2.57; mean change in the TAU arm: 0.86; Cohen's
= 0.97, 95% confidence interval (CI) 0.75 to 1.19, corroborated by carer ratings (Cohen's
= 1.11, 95% CI 0.89 to 1.34). These effects were maintained at 9 months for both the participant ratings (Cohen's
= 0.94, 95% CI 0.71 to 1.17) and the carer ratings (Cohen's
= 0.96, 95% CI 0.73 to 1.20). There were no significant differences in the secondary outcomes. In the cost-utility analyses, there was no evidence of cost-effectiveness in terms of gains in the quality-adjusted life-years (QALYs) of the person with dementia (measured using the DEMentia Quality Of Life questionnaire utility score) or the QALYs of the carer (measured using the EuroQol-5 Dimensions, three-level version) from either cost perspective. In the cost-effectiveness analyses, by reference to the primary outcome of participant-rated goal attainment, CR was cost-effective from both the health and social care perspective and the societal perspective at willingness-to-pay values of £2500 and above for improvement in the goal attainment measure. There was no evidence on the cost-effectiveness of the self-efficacy measure (the Generalized Self-Efficacy Scale) from either cost perspective.
Possible limitations arose from the non-feasibility of using observational outcome measures, the lack of a general measure of functional ability and the exclusion of people without a carer or with rarer forms of dementia.
Cognitive rehabilitation is clinically effective in enabling people with early-stage dementia to improve their everyday functioning in relation to individual goals targeted in the therapy sessions.
Next steps will focus on the implementation of CR into NHS and social care services and on extending the approach to people with rarer forms of dementia.
Current Controlled Trials ISRCTN21027481.
This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in
; Vol. 23, No. 10. See the NIHR Journals Library website for further project information.
The vast majority of brain-injured patients with semantic impairment have better comprehension of concrete than abstract words. In contrast, several patients with semantic dementia (SD), who show ...circumscribed atrophy of the anterior temporal lobes bilaterally, have been reported to show
reverse
imageability effects, that is, relative preservation of abstract knowledge. Although these reports largely concern individual patients, some researchers have recently proposed that superior comprehension of abstract concepts is a characteristic feature of SD. This would imply that the anterior temporal lobes are particularly crucial for processing sensory aspects of semantic knowledge, which are associated with concrete not abstract concepts. However, functional neuroimaging studies of healthy participants do not unequivocally predict reverse imageability effects in SD because the temporal poles sometimes show greater activation for more abstract concepts. The authors examined a case-series of 11 SD patients on a synonym judgment test that orthogonally varied the frequency and imageability of the items. All patients had higher success rates for more imageable as well as more frequent words, suggesting that (1) the anterior temporal lobes underpin semantic knowledge for both concrete and abstract concepts, (2) more imageable items-perhaps because of their richer multimodal representations-are typically more robust in the face of global semantic degradation and (3) reverse imageability effects are not a characteristic feature of SD.
Objective To investigate the pattern and trends of use of antipsychotics, antidepressants, hypnotics and anxiolytics in Alzheimer's disease and other dementias and in patients treated with ...antidementia medications. Design Cohort study with dementia patients formed in the UK Clinical Practice Research Datalink. Participants Patients with incident dementia, between 1995 and 2011 and a reference non-dementia cohort matched on age, gender and date of dementia diagnosis. Two subcohorts included new users of acetylcholinesterase inhibitors (AChEIs) and memantine. The study endpoint was use of antipsychotics, antidepressants, hypnotics and anxiolytics up to 10 years before and 4 years after dementia diagnosis, and for up to 5 years before and 1 year after first use of AChEI or memantine. Results 50 349 patients with incident dementia diagnosis and 50 349 matched controls, 10 794 first-time users of AChEI and 669 of memantine. The mean prevalence of antipsychotic use from 1995 to 2011 on diagnosis of dementia was 12.5%, decreasing from 19.9% in 1995 to 7.4% in 2011. There was an increase in antidepressant use (10.7–26.3%) and a small increase in anxiolytic use. The matched cohort showed a lower use of antipsychotics and anxiolytics but a rise in antidepressants (5.9–13.4%). Both groups showed a decrease in hypnotic use. 10.6% of AChEI and 26.3% of memantine users were prescribed antipsychotics, 34.1% and 26.3% antidepressants, 13.2% and 4.1% anxiolytics and 18.4% and 8.3% hypnotics. The slopes for monthly use of antipsychotics were positive in the year leading up to AChEI and memantine use; after treatment initiation the slope for AChEI users continued to increase but at a reduced rate whereas antipsychotic use declined for memantine users. Conclusions The marked reduction in antipsychotic use in dementia is to be welcomed while there was a steady increase in antidepressant use. There was a decline in antipsychotic use after the initiation of memantine.
Objectives
To determine whether individual goal‐oriented cognitive rehabilitation (CR) improves everyday functioning for people with mild‐to‐moderate dementia.
Design and methods
Parallel group ...multicentre single‐blind randomised controlled trial (RCT) comparing CR added to usual treatment (CR) with usual treatment alone (TAU) for people with an ICD‐10 diagnosis of Alzheimer, vascular or mixed dementia, and mild‐to‐moderate cognitive impairment (Mini‐Mental State Examination MMSE score ≥ 18), and with a family member willing to contribute. Participants allocated to CR received 10 weekly sessions over 3 months and four maintenance sessions over 6 months. Participants were followed up 3 and 9 months post randomisation by blinded researchers. The primary outcome was self‐reported goal attainment at 3 months. Secondary outcomes at 3 and 9 months included informant‐reported goal attainment, quality of life, mood, self‐efficacy, and cognition and study partner stress and quality of life.
Results
We randomised (1:1) 475 people with dementia; 445 (CR = 281) were included in the intention to treat analysis at 3 months and 426 (CR = 208) at 9 months. At 3 months, there were statistically significant large positive effects for participant‐rated goal attainment (d = 0.97; 95% CI, 0.75‐1.19), corroborated by informant ratings (d = 1.11; 95% CI, 0.89‐1.34). These effects were maintained at 9 months for both participant (d = 0.94; 95% CI, 0.71‐1.17) and informant (d = 0.96; 95% CI, 0.73‐1.2) ratings. The observed gains related to goals directly targeted in the therapy. There were no significant differences in secondary outcomes.
Conclusions
CR enables people with early‐stage dementia to improve their everyday functioning in relation to individual goals targeted in the therapy.
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