Explore the vast range of titles available.

Tests sensitive to presymptomatic changes in Alzheimer's disease could be valuable for clinical trials. Accelerated long-term forgetting—during which memory impairment becomes apparent over longer periods than usually assessed, despite normal performance on standard cognitive testing—has been identified in other temporal lobe disorders. We assessed whether accelerated long-term forgetting is a feature of presymptomatic autosomal dominant (familial) Alzheimer's disease, and whether there is an association between accelerated long-term forgetting and early subjective memory changes. This was a cross-sectional study at the Dementia Research Centre, University College London (London, UK). Participants were recruited from a cohort of autosomal dominant Alzheimer's disease families already involved in research at University College London, and had to have a parent known to be affected by an autosomal dominant Alzheimer's disease mutation, and not report any current symptoms of cognitive decline. Accelerated long-term forgetting of three tasks (list, story, and figure recall) was assessed by comparing 7-day recall with initial learning and 30-min recall. 7-day recognition was also assessed. Subjective memory was assessed using the Everyday Memory Questionnaire. The primary outcome measure for each task was the proportion of material retained at 30 min that was recalled 7 days later (ie, 7-day recall divided by 30-min recall). We used linear regression to compare accelerated long-term forgetting scores between mutation carriers and non-carriers (adjusting for age, IQ, and test set) and, for mutation carriers, to assess whether there was an association between accelerated long-term forgetting and estimated years to symptom onset (EYO). Spearman's correlation was used to examine the association between accelerated long-term forgetting and subjective memory scores. Between Feb 17, 2015 and March 30, 2016, we recruited 35 people. 21 participants were mutation carriers (mean EYO 7·2 years, SD 4·5). Across the three tasks, we detected no differences between carriers and non-carriers for initial learning or 30-min recall. The proportion of material recalled at 7 days was lower in carriers than non-carriers for list (estimated difference in mean for list recall −30·94 percentage points, 95% CI −45·16 to −16·73; p=0·0002), story (–20·10, −33·28 to −6·91; p=0·0048), and figure (–15·41, −26·88 to −3·93; p=0·012) recall. Accelerated long-term forgetting was greater in carriers nearer to their estimated age at onset (p≤0·01 for all three tests). Mutation carriers' 7-day recognition memory was also lower across all tasks (list [mean difference −5·80, 95% CI −9·96 to −2·47; p<0·01], story [–6·84, −10·94 to −3·37; p<0·01], and figure [–17·61, −27·68 to −7·72; p<0·01] recognition). Subjective memory scores were poorer in asymptomatic carriers compared with non-carriers (adjusted difference in means 7·88, 95% CI 1·36 to 14·41; p=0·016), and we found a correlation between accelerated long-term forgetting and subjective memory in mutation carriers. Accelerated long-term forgetting is an early presymptomatic feature of autosomal dominant Alzheimer's disease, which appears to pre-date other amnestic deficits and might underpin subjective memory complaints in Alzheimer's disease. Accelerated long-term forgetting testing might be useful in presymptomatic Alzheimer's disease trials. MRC, NIHR, Alzheimer's Research UK, Dementias Platform UK, Dunhill Medical Trust, ERUK, Great Western Research, Health Foundation, Patrick Berthoud Trust.

Regioselective reactions can play pivotal roles in synthetic organic chemistry. The reduction of several 1-substituted 1,2,3-triazole 4,5-diesters by sodium borohydride has been found to be regioselective, with the C(5) ester groups being more reactive towards reduction than the C(4) ester groups. The amount of sodium borohydride and reaction time required for reduction varied greatly depending on the N(1)-substituent. The presence of a β-hydroxyl group on the N(1)-substituent was seen to have a rate enhancing effect on the reduction of the C(5) ester group. The regioselective reduction was attributed to the lower electron densities of the C(5) and the C(5) ester carbonyl carbon of the 1,2,3-triazole, which were further lowered in cases involving intramolecular hydrogen bonding.

Rodent and human data implicate the hippocampus in the arbitration of approach-avoidance conflict (AAC), which arises when an organism is confronted with a stimulus associated simultaneously with reward and punishment. Yet, the precise contributions of this structure are underexplored, particularly with respect to the decision-making processes involved. We assessed humans with hippocampal damage and matched neurologically healthy controls on a computerized AAC paradigm in which participants first learned whether individual visual images were associated with the reward or loss of game points and were then asked to approach or avoid pairs of stimuli with non-conflicting or conflicting valences. To assess hippocampal involvement more broadly in response conflict, we also administered a Stroop and a Go/No-go task. On the AAC paradigm, following similar learning outcomes in individuals with hippocampal damage and matched controls, both participant groups approached positive and negative image pairs at the same rate but critically, those with hippocampal damage approached conflict pairs more often than controls. Choice and response AAC data were interrogated using the hierarchical drift diffusion model, which revealed that, compared to controls, individuals with hippocampal damage were more biased towards approach, required less evidence to make a decision during conflict trials, and were slower to accumulate evidence towards avoidance when confronted with conflicting image pairs. No significant differences were found between groups in performance accuracy or response time on the response conflict tasks. Taken together, these findings demonstrate the importance of the hippocampus to the evidence accumulation processes supporting value-based decision-making under motivational conflict.

Posterior cortical atrophy (PCA) is a neurodegenerative syndrome characterized by progressive impairment in visuospatial and perceptual function linked to atrophy of the occipito-parietal cortex. Besides the salient visual impairment, several studies have documented subtle changes in language may also be present. Sentence repetition is a highly constrained linguistic task involving multiple linguistic and cognitive processes and have been shown to be impaired in other AD spectrum disorders, with little consensus on its relevance in PCA. This aim of this study was to further delineate the linguistic and cognitive features of impaired language in PCA using a sentence repetition task. Seven PCA patients and 16 healthy controls verbally repeated 16 sentences from the Boston Diagnostic Aphasia Examination. Responses were transcribed orthographically and coded for accuracy (percentage accuracy; percentage Correct Information Units; Levenshtein Distance) and for temporal characteristics (preparation duration (ms); utterance duration (ms); silent pause duration (ms); speech duration (ms); dysfluency duration (ms)). The potential modulating effects of attentional control and working memory capacity were explored. PCA patients showed lower overall accuracy with retained semantic content of the sentences, and lower phonological accuracy. Temporal measures revealed longer preparation and utterance duration for PCA patients compared to controls, alongside longer speech duration but comparable dysfluency duration. PCA patients also showed comparable silent pause duration to controls. Attentional control, measured using the Hayling sentence completion task, predicted accuracy of sentence repetition. The findings suggest that sentence repetition is impaired in PCA and is characterized by phonological, response planning and execution difficulties, underpinned in part by attentional control mechanisms. The emerging profile of language impairment in PCA suggests vulnerability of similar cognitive systems to other Alzheimer's syndromes, with subtle differences in clinical presentation.

Patients with hippocampal amnesia play a central role in memory neuroscience but the neural underpinnings of amnesia are hotly debated. We hypothesized that focal hippocampal damage is associated with changes across the extended hippocampal system and that these, rather than hippocampal atrophy per se, would explain variability in memory between patients. We assessed this hypothesis in a uniquely large cohort of patients (n = 38) after autoimmune limbic encephalitis, a syndrome associated with focal structural hippocampal pathology. These patients showed impaired recall, recognition and maintenance of new information, and remote autobiographical amnesia. Besides hippocampal atrophy, we observed correlatively reduced thalamic and entorhinal cortical volume, resting-state inter-hippocampal connectivity and activity in posteromedial cortex. Associations of hippocampal volume with recall, recognition, and remote memory were fully mediated by wider network abnormalities, and were only direct in forgetting. Network abnormalities may explain the variability across studies of amnesia and speak to debates in memory neuroscience.

IntroductionDementia is a chronic and progressive neurological condition characterised by cognitive and functional impairment. It is often associated with multimorbidity and imposes a significant economic burden on healthcare systems and families, especially in low-income and middle-income countries. In Peru, where dementia cases are increasing rapidly, timely detection and referral for diagnosis is crucial. This protocol is part of the IMPACT Salud project in Peru. Here, we focus on a specific component aimed at validating an mHealth tool for the detection of cognitive and functional impairment and assessing its cost-effectiveness. We will also assess changes in cognitive and functional impairment as well as health economic outcomes over 1 year.Methods and analysisThis observational study will be conducted in four geographically diverse regions of Peru. Community health workers are expected to contact approximately 32 000 participants (≥60 years) to apply an mHealth-enabled tool that includes cognitive and functional instruments: Ascertain Dementia 8, Peruvian version of Rowland Universal Dementia Assessment Scale and Pfeffer Functional Activities Questionnaire. From this large sample, we aim to find 3600 participants and their study partners to enrol and interview at baseline regarding sociodemographic characteristics, lifestyles, comorbidities and health economic data including resource use, costs and health-related quality of life (HR-QoL). Psychologists, blind to previous results, will assess dementia stage of the participants using an abbreviated Clinical Dementia Rating (CDR) scale. At 6-month follow-up, participants will complete a brief health economics questionnaire on resource use, costs and HR-QoL. To validate the accuracy of the detection tool, a subsample of 600 participants who completed the baseline will undergo a gold-standard clinical neuropsychological assessment. This subsample will participate in a 12-month follow-up, including health economics, cognitive and functional impairment tests and the CDR scale. Results will be analysed and presented by cognitive status, site, sex and multimorbidity profile. Finally, data from all stages and external sources will inform a decision model to implement a cost-effectiveness analysis of the detection tool at the national level.Ethics and disseminationThe study received ethics approval in Peru (Universidad Peruana Cayetano Heredia: CONSTANCIA-CIEI-378-33-23) and in the UK (Imperial College London: ICREC/SETREC reference number 6647445). Informed consent will be obtained from participants and their study partners, considering the participant’s capacity to consent. For illiterate participants, consent will be obtained through a witnessed procedure involving study partners, with a fingerprint obtained instead of a signature. The results will be disseminated through conferences, published articles, public presentations (particularly to those involved in dementia care) and presentations or meetings with local health authorities.

Background Current clustering of multimorbidity based on the frequency of common disease combinations is inadequate. We estimated the causal relationships among prevalent diseases and mapped out the clusters of multimorbidity progression among them. Methods In this cohort study, we examined the progression of multimorbidity among 190 diseases among over 500,000 UK Biobank participants over 12.7 years of follow-up. Using a machine learning method for causal inference, we analyzed patterns of how diseases influenced and were influenced by others in females and males. We used clustering analysis and visualization algorithms to identify multimorbidity progress constellations. Results We show the top influential and influenced diseases largely overlap between sexes in chronic diseases, with sex-specific ones tending to be acute diseases. Patterns of diseases that influence and are influenced by other diseases also emerged (clustering significance P au  > 0.87), with the top influential diseases affecting many clusters and the top influenced diseases concentrating on a few, suggesting that complex mechanisms are at play for the diseases that increase the development of other diseases while share underlying causes exist among the diseases whose development are increased by others. Bi-directional multimorbidity progress presents substantial clustering tendencies both within and across International Classification Disease chapters, compared to uni-directional ones, which can inform future studies for developing cross-specialty strategies for multimorbidity. Finally, we identify 10 multimorbidity progress constellations for females and 9 for males (clustering stability, adjusted Rand index >0.75), showing interesting differences between sexes. Conclusion Our findings could inform the future development of targeted interventions and provide an essential foundation for future studies seeking to improve the prevention and management of multimorbidity. Plain language summary Mapping out clusters of diseases is crucial to addressing the rising challenge of co-occurrence of multiple diseases, known as multimorbidity. However, the current way of grouping diseases based on their associations isn’t enough to understand how they develop over time. We’ve come up with a new approach to map out how groups of diseases progress together based on the strength of their causal relationships. By looking at how each disease affects the development of others, we can get a better understanding of how they form clusters. Our research goes beyond just showing which diseases occur together, and it’s a step toward improving how we prevent and manage multiple health conditions in the future. Han et al. present a framework to map the clusters of multimorbidity progression by examining the bi-directional causal progress between hundreds of diseases. This provides a comprehensive picture of how one disease influences and is influenced by the development of others, and how they form clusters of disease trajectories.

In The Lancet Neurology, Philip Weston and colleagues report that presymptomatic individuals carrying familial Alzheimer's disease gene mutations demonstrate accelerated long-term forgetting over an extended 1 week retention interval compared with gene-negative controls.1 These findings raise the question of whether accelerated long-term forgetting is also detectable in presymptomatic individuals at genetic risk of the much more common sporadic form of Alzheimer's disease. In white people, risk of Alzheimer's disease is 15 times higher among homozygous ε4 carriers (with two copies of the ε4 allele) and three times higher among heterozygous carriers (with one copy each of the ε3 and ε4 alleles) compared with ε4 non-carriers.2 Standard memory tests show longitudinal differentiation according to APOE genotype at around 60 years of age,3 but evidence from cross-sectional studies of pre-symptomatic individuals at this age or earlier is inconclusive.4 We recruited 60 healthy white English-fluent participants—20 homozygous for ε4, 20 heterozygous for ε3 and ε4, and 20 homozygous for ε3—between 40 and 60 years of age (appendix). Taken together, these findings suggest that APOE ε4 confers a specific impairment of long-term memory storage dependent on the number of copies of the allele rather than an impairment of memory encoding or retrieval.

Dementia imposes a significant economic burden worldwide, particularly in low- and middle-income countries (LMICs), where the majority of people with dementia (PWD) live. Understanding the costs of dementia and resource utilisation is essential to inform future cost-effectiveness analyses and economic modelling. We aimed to describe and analyse resource utilisation and costs across all stages of dementia in LMICs. We conducted a systematic review following a PROSPERO-registered protocol (CRD42017071413). We identified studies using patient-level data, published between 1 January 2000 and 14 August 2023, across several databases and registries. Data were selected, extracted, and quality appraised by two independent reviewers. The main outcomes were resource utilisation and cost per PWD. Outcomes were annualised and reported as total costs, by cost category and disease stage. Costs were adjusted for inflation and converted to international dollars using 2024 purchasing power parities (PPP). We assessed quality using a shortened version of the BMJ guidelines. The review included 23 studies, of which 21 provided unique patient-level datasets, covering 14 countries and 14,392 PWD. Resource utilisation was not reported separately in most studies, and results varied widely: inpatient admissions ranged from 0 to 4.9 per year, outpatient visits from 0.4 to 14.9 per year, and informal caregiver time from 0.2 to 17.9 hours/day. Only 43% reported the mean annual total cost per PWD by disease stage. Mean annual total cost per PWD, irrespective of dementia stage, ranged from 4,658 to 37,887 USD PPP. Greater variation was observed across stages: from 1,316 to 27,438 USD PPP in mild dementia; 3,981 to 36,637 USD PPP in moderate; and from 7,520 to 51,456 USD PPP in severe dementia. Costs in severe dementia often doubled those in earlier stages. Few studies reported caregivers' productivity losses, and none included pre-dementia or end-of-life stages. Resource utilisation and costs of dementia increased substantially with disease progression, but the reporting of both outcomes was highly heterogeneous. There is an urgent need to improve the quality of reporting in studies from LMICs. Further research using patient-level data is needed, given that only 10% of LMICs had at least one study.

Background Dementia imposes a significant economic burden worldwide, particularly in low‐ and middle‐income countries (LMICs), where the majority of people with dementia (PWD) live. Understanding the costs of dementia and resource utilisation is essential to inform future cost‐effectiveness analyses and economic modelling. We aimed to describe and analyse resource utilisation and costs across all stages of dementia in LMICs. Method We conducted a systematic review following a PROSPERO‐registered protocol (CRD42017071413). We identified studies using patient‐level data, published between 1 January 2000 and 14 August 2023, across several databases and registries. Data were selected, extracted, and quality appraised by two independent reviewers. The main outcomes were resource utilisation and cost per PWD. Outcomes were annualised and reported as total costs, by cost category and disease stage. Costs were adjusted for inflation and converted to international dollars using 2024 purchasing power parities (PPP). We assessed quality using a shortened version of the BMJ guidelines. Result The review included 23 studies, of which 21 provided unique patient‐level datasets, covering 14 countries and 14,392 PWD. Resource utilisation was not reported separately in most studies, and results varied widely: inpatient admissions ranged from 0 to 4.9 per year, outpatient visits from 0.4 to 14.9 per year, and informal caregiver time from 0.2 to 17.9 hours/day. Only 43% reported the mean annual total cost per PWD by disease stage. Mean annual total cost per PWD, irrespective of dementia stage, ranged from 4,658 to 37,887 USD PPP. Greater variation was observed across stages: from 1,316 to 27,438 USD PPP in mild dementia; 3,981 to 36,637 USD PPP in moderate; and from 7,520 to 51,456 USD PPP in severe dementia. Costs in severe dementia often doubled those in earlier stages. Few studies reported caregivers’ productivity losses, and none included pre‐dementia or end‐of‐life stages. Conclusion Resource utilisation and costs of dementia increased substantially with disease progression, but the reporting of both outcomes was highly heterogeneous. There is an urgent need to improve the quality of reporting in studies from LMICs. Further research using patient‐level data is needed, given that only 10% of LMICs had at least one study.