ObjectivesWe explored whether adapting neuropsychological tests for online administration during the COVID-19 pandemic was feasible for dementia research.DesignWe used a longitudinal design for ...healthy controls, who completed face-to-face assessments 3–4 years before remote assessments. For patients, we used a cross-sectional design, contrasting a prospective remote cohort with a retrospective face-to-face cohort matched for age/education/severity.SettingRemote assessments were conducted using video-conferencing/online testing platforms, with participants using a personal computer/tablet at home. Face-to-face assessments were conducted in testing rooms at our research centre.ParticipantsThe remote cohort comprised 25 patients (n=8 Alzheimer’s disease (AD); n=3 behavioural variant frontotemporal dementia (bvFTD); n=4 semantic dementia (SD); n=5 progressive non-fluent aphasia (PNFA); n=5 logopenic aphasia (LPA)). The face-to-face patient cohort comprised 64 patients (n=25 AD; n=12 bvFTD; n=9 SD; n=12 PNFA; n=6 LPA). Ten controls who previously participated in face-to-face research also took part remotely.Outcome measuresThe outcome measures comprised the strength of evidence under a Bayesian framework for differences in performances between testing environments on general neuropsychological and neurolinguistic measures.ResultsThere was substantial evidence suggesting no difference across environments in both the healthy control and combined patient cohorts (including measures of working memory, single-word comprehension, arithmetic and naming; Bayes Factors (BF)01 >3), in the healthy control group alone (including measures of letter/category fluency, semantic knowledge and bisyllabic word repetition; all BF01 >3), and in the combined patient cohort alone (including measures of working memory, episodic memory, short-term verbal memory, visual perception, non-word reading, sentence comprehension and bisyllabic/trisyllabic word repetition; all BF01 >3). In the control cohort alone, there was substantial evidence in support of a difference across environments for tests of visual perception (BF01=0.0404) and monosyllabic word repetition (BF01=0.0487).ConclusionsOur findings suggest that remote delivery of neuropsychological tests for dementia research is feasible.
Although age is the biggest known risk factor for dementia, there remains uncertainty about other factors over the life course that contribute to a person's risk for cognitive decline later in life. ...Furthermore, the pathological processes leading to dementia are not fully understood. The main goals of Insight 46-a multi-phase longitudinal observational study-are to collect detailed cognitive, neurological, physical, cardiovascular, and sensory data; to combine those data with genetic and life-course information collected from the MRC National Survey of Health and Development (NSHD; 1946 British birth cohort); and thereby contribute to a better understanding of healthy ageing and dementia.
Phase 1 of Insight 46 (2015-2018) involved the recruitment of 502 members of the NSHD (median age = 70.7 years; 49% female) and has been described in detail by Lane and Parker et al. 2017. The present paper describes phase 2 (2018-2021) and phase 3 (2021-ongoing). Of the 502 phase 1 study members who were invited to a phase 2 research visit, 413 were willing to return for a clinic visit in London and 29 participated in a remote research assessment due to COVID-19 restrictions. Phase 3 aims to recruit 250 study members who previously participated in both phases 1 and 2 of Insight 46 (providing a third data time point) and 500 additional members of the NSHD who have not previously participated in Insight 46.
The NSHD is the oldest and longest continuously running British birth cohort. Members of the NSHD are now at a critical point in their lives for us to investigate successful ageing and key age-related brain morbidities. Data collected from Insight 46 have the potential to greatly contribute to and impact the field of healthy ageing and dementia by combining unique life course data with longitudinal multiparametric clinical, imaging, and biomarker measurements. Further protocol enhancements are planned, including in-home sleep measurements and the engagement of participants through remote online cognitive testing. Data collected are and will continue to be made available to the scientific community.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The study investigated whether donepezil exerts symptomatic benefit in patients with posterior cortical atrophy (PCA), an atypical variant of Alzheimer's disease.
A single-centre, double-blind, ...placebo-controlled, cross-over clinical trial was performed to assess the efficacy of donepezil in patients with PCA. Each patient received either donepezil (5 mg once daily in the first 6 weeks and 10 mg once daily in the second 6 weeks) or placebo for 12 weeks. After a 2-week washout period, each patient received the other treatment arm during the following 12 weeks followed by another 2-week washout period. The primary outcome was the Mini-Mental State Examination (MMSE) at 12 weeks. Secondary outcome measures were five neuropsychological tests reflecting parieto-occipital function. Intention-to-treat analysis was used. For each outcome measure, carry-over effects were first assessed. If present, then analysis was restricted to the first 12-week period. Otherwise, the standard approach to the analysis of a 2 × 2 cross-over trial was used.
Eighteen patients (13 females) were recruited (mean age 61.6 years). There was a protocol violation in one patient, who subsequently withdrew from the study due to gastrointestinal side effects. There was statistically significant (p < 0.05) evidence of a carry-over effect on MMSE. Therefore, the analysis of treatment effect on MMSE was restricted to the first 12-week period. Treatment effect at 6 weeks was statistically significant (difference = 2.5 in favour of donepezil, 95% CI 0.1 to 5.0, p < 0.05). Treatment effect at 12 weeks was close, but not statistically significant (difference = 2.0 in favour of donepezil, 95% CI -0.1 to 4.5, p > 0.05). There were no statistically significant treatment effects on any of the five neuropsychological tests, except for digit span at 12 weeks (higher by 0.5 digits in favour of placebo, 95% CI 0.1 to 0.9). Gastrointestinal side effects occurred most frequently, affecting 13/18 subjects (72%), and were the cause of study discontinuation in one subject. Nightmares and vivid dreams occurred in 8/18 subjects (44%), and were statistically more frequent during treatment with donepezil.
In this small study, there was no statistically significant treatment effect of donepezil on the primary outcome measure (MMSE score at 12 weeks) in PCA patients, who appear to be particularly susceptible to the development of nightmares and vivid dreams when treated.
Trial registration: Current Controlled Trials ISRCTN22636071 . Retrospectively registered 19 May 2010.
Blood biomarkers have great potential to advance clinical care and accelerate trials in Alzheimer's disease (AD). Plasma phospho-tau181 (p-tau181) is a promising blood biomarker however, it is ...unknown if levels increase in presymptomatic AD. Therefore, we investigated the timing of p-tau181 changes using 153 blood samples from 70 individuals in a longitudinal study of familial AD (FAD). Plasma p-tau181 was measured, using an in-house single molecule array assay. We compared p-tau181 between symptomatic carriers, presymptomatic carriers, and non-carriers, adjusting for age and sex. We examined the relationship between p-tau181 and neurofilament light and estimated years to/from symptom onset (EYO), as well as years to/from actual onset in a symptomatic subgroup. In addition, we studied associations between p-tau181 and clinical severity, as well testing for differences between genetic subgroups. Twenty-four were presymptomatic carriers (mean baseline EYO -9.6 years) while 27 were non-carriers. Compared with non-carriers, plasma p-tau181 concentration was higher in both symptomatic (p < 0.001) and presymptomatic mutation carriers (p < 0.001). Plasma p-tau181 showed considerable intra-individual variability but individual values discriminated symptomatic (AUC 0.93 95% CI 0.85-0.98) and presymptomatic (EYO ≥ -7 years) (AUC 0.86 95% CI 0.72-0.94) carriers from non-carriers of the same age and sex. From a fitted model there was evidence (p = 0.050) that p-tau181 concentrations were higher in mutation carriers than non-carriers from 16 years prior to estimated symptom onset. Our finding that plasma p-tau181 concentration is increased in symptomatic and presymptomatic FAD suggests potential utility as an easily accessible biomarker of AD pathology.
We have developed efficient synthetic routes to two hydrophobic amino acids, suitably protected for solid-phase peptide synthesis, and have successfully synthesized peptides containing these or other ...hydrophobic amino acids as spacers between a Lys16 moiety and an integrin-targeting motif. These peptides have in turn been used to formulate a range of lipopolyplex vectors with Lipofectin and plasmid DNA. The transfection efficiencies of these vectors and their aggregation behavior in buffers and in serum have been studied. We have shown that vectors containing peptides incorporating long linkers that are entirely hydrophobic are less efficient transfection agents. However, linkers of equivalent length that are in part hydrophobic show improved transfection properties, which is probably due to the improved accessibility of the integrin-binding motif.
Rare Dementia Support (RDS) is a UK‐based collaborative service led by the UCL Dementia Research Centre, which aims to empower, guide and inform people living with a rare dementia diagnosis and those ...who care about them. RDS covers familial Alzheimer’s disease (FAD), frontotemporal dementia (FTD), familial frontotemporal dementia (fFTD), posterior cortical atrophy (PCA), primary progressive aphasia (PPA), Lewy body dementia (LBD) and young‐onset Alzheimer’s disease (YOAD). Following self‐referrals and clinical referrals from memory services and specialist neurology clinics across the UK, we provide one‐to‐one support and facilitate regular opportunities for members to meet each other and the team, through large and small support groups, themed programmes and regional support groups.
We will describe the practices of the one‐to‐one Direct Support Team, which provides free information, advice and support from pre‐diagnosis navigation through to post‐bereavement support. This specialist emotional and practical support encompasses compassionate listening; solution focussed outcomes (to complement the diagnosis, treatment and monitoring); helping people to understand and adapt to their condition; empowering people to use their strengths to live fulfilled lives; designing strategies and interventions to manage complex situations (including issues of safeguarding, deprivation of liberty, etc); legal rights and financial support; and supporting transitions into later stages and end of life.
We will also relate the practices of direct support to the broader principles of RDS as a whole (see Figure 1), including the implications of never discharging anyone from our service, and balancing person‐centred and disease‐specific approaches (the importance of knowing which disease each person has, and what person the disease has).
An evaluation of the service will be presented, including characterisation of the current 4797 members, plus data from individual support consultations in 2022 (N = 1449) relating outcomes to personal (social connectedness, wellbeing, knowledge of condition and services), disease (diagnosis, severity) and service (support usage, intensity of discussion) factors.
We will conclude by discussing existing examples of and new opportunities for partnership working – with local, national and international charities, clinical services, academic institutions and funding organisations – to improve access to specialist support for those with atypical, inherited and young onset dementias.
Objectives
The Rare Dementia Support (RDS) Impact study will be the first major study of the value of multicomponent support groups for people living with or supporting someone with a rare form of ...dementia. The multicentre study aims to evaluate the impact of multicomponent support offered and delivered to people living with a rare form of dementia, comprising the following five work packages (WPs): (a) longitudinal cohort interviews, (b) theoretical development, (c) developing measures, (d) novel interventions, and (e) economic analysis.
Methods
This is a mixed‐methods design, including a longitudinal cohort study (quantitative and qualitative) and a feasibility randomised control trial (RCT). A cohort of more than 1000 individuals will be invited to participate. The primary and secondary outcomes will be in part determined through a co‐design nominal groups technique prestudy involving caregivers to people living with a diagnosis of a rare dementia. Quantitative analyses of differences and predictors will be based on prespecified hypotheses. A variety of quantitative (eg, analysis of variance ANOVA and multiple linear regression techniques), qualitative (eg, thematic analysis TA), and innovative analytical methods will also be developed and applied by involving the arts as a research method.
Results
The UCL Research Ethics Committee have approved this study. Data collection commenced in January 2020.
Conclusions
The study will capture information through a combination of longitudinal interviews, questionnaires and scales, and novel creative data collection methods. The notion of “impact” in the context of support for rare dementias will involve theoretical development, novel measures and methods of support interventions, and health economic analyses.
INTRODUCTION
Here we set out to create a symptom‐led staging system for the canonical semantic and non‐fluent/agrammatic variants of primary progressive aphasia (PPA), which present unique diagnostic ...and management challenges not well captured by functional scales developed for Alzheimer's disease and other dementias.
METHODS
An international PPA caregiver cohort was surveyed on symptom development under six provisional clinical stages and feedback was analyzed using a mixed‐methods sequential explanatory design.
RESULTS
Both PPA syndromes were characterized by initial communication dysfunction and non‐verbal behavioral changes, with increasing syndromic convergence and functional dependency at later stages. Milestone symptoms were distilled to create a prototypical progression and severity scale of functional impairment: the PPA Progression Planning Aid (“PPA‐Squared”).
DISCUSSION
This work introduces a symptom‐led staging scheme and functional scale for semantic and non‐fluent/agrammatic variants of PPA. Our findings have implications for diagnostic and care pathway guidelines, trial design, and personalized prognosis and treatment for PPA.
Highlights
We introduce new symptom‐led perspectives on primary progressive aphasia (PPA).
The focus is on non‐fluent/agrammatic (nfvPPA) and semantic (svPPA) variants.
Foregrounding of early and non‐verbal features of PPA and clinical trajectories is featured.
We introduce a symptom‐led staging scheme for PPA.
We propose a prototype for a functional impairment scale, the PPA Progression Planning Aid.
Background and purpose
Logopenic variant primary progressive aphasia (lvPPA) is a major variant presentation of Alzheimer's disease (AD) that signals the importance of communication dysfunction ...across AD phenotypes. A clinical staging system is lacking for the evolution of AD‐associated communication difficulties that could guide diagnosis and care planning. Our aim was to create a symptom‐based staging scheme for lvPPA, identifying functional milestones relevant to the broader AD spectrum.
Methods
An international lvPPA caregiver cohort was surveyed on symptom development under an ‘exploratory’ survey (34 UK caregivers). Feedback from this survey informed the development of a ‘consolidation’ survey (27 UK, 10 Australian caregivers) in which caregivers were presented with six provisional clinical stages and feedback was analysed using a mixed‐methods approach.
Results
Six clinical stages were endorsed. Early symptoms included word‐finding difficulty, with loss of message comprehension and speech intelligibility signalling later‐stage progression. Additionally, problems with hearing in noise, memory and route‐finding were prominent early non‐verbal symptoms. ‘Milestone’ symptoms were identified that anticipate daily‐life functional transitions and care needs.
Conclusions
This work introduces a new symptom‐based staging scheme for lvPPA, and highlights milestone symptoms that could inform future clinical scales for anticipating and managing communication dysfunction across the AD spectrum.
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