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Objective Systematically review and critically appraise the evidence for the association between delirium and falls in community-dwelling adults aged ≥60 years. Methods We searched EMBASE, MEDLINE, PsycINFO, Cochrane Database of Systematic Reviews, CINAHL and Evidence-Based Medicine Reviews databases in April 2023. Standard methods were used to screen, extract data, assess risk of bias (using Newcastle–Ottawa scale), provide a narrative synthesis and, where appropriate, conduct meta-analysis. Results We included 8 studies, with at least 3505 unique participants. Five found limited evidence for an association between delirium and subsequent falls: one adjusted study showed an increase in falls (risk ratio 6.66; 95% confidence interval (CI) 2.16–20.53), but the evidence was low certainty. Four non-adjusted studies found no clear effect. Three studies (one with two subgroups treated separately) found some evidence for an association between falls and subsequent delirium: meta-analysis of three adjusted studies showed an increase in delirium (pooled odds ratio 2.01; 95% CI 1.52–2.66); one subgroup of non-adjusted data found no clear effect. Number of falls and fallers were reported in the studies. Four studies and one subgroup were at high risk of bias and one study had some concerns. Conclusions We found limited evidence for the association between delirium and falls. More methodologically rigorous research is needed to understand the complex relationship and establish how and why this operates bidirectionally. Studies must consider confounding factors such as dementia, frailty and comorbidity in their design, to identify potential modifying factors involved. Clinicians should be aware of the potential relationship between these common presentations. [ABSTRACT FROM AUTHOR]

There are national and global moves to improve effective digital data design and application in healthcare. This New Horizons commentary describes the role of digital data in healthcare of the ageing population. We outline how health and social care professionals can engage in the proactive design of digital systems that appropriately serve people as they age, carers and the workforce that supports them. Key Points Healthcare improvements have resulted in increased population longevity and hence multimorbidity. Shared care records to improve communication and information continuity across care settings hold potential for older people. Data structure and coding are key considerations. A workforce with expertise in caring for older people with relevant knowledge and skills in digital healthcare is important. [ABSTRACT FROM AUTHOR]

Delirium affects 25% of hospital admissions of older people and is a serious medical condition with poor outcomes. 'New confusion' as a delirium indicator was incorporated into the 'alert, verbal, pain and unresponsive' (AVPU) level of consciousness scale in the National Early Warning Score 2 (NEWS2) in 2017. We measured sensitivity of non-alert NEWS2 (new confusion and/or V, P or U ratings) for delirium through comparison with the four 'A's test (4AT) delirium tool in 13,908 consecutive non-elective hospital admissions. We included NEWS2 scores 4 hours before or after 4AT. There were 2,802 (20%) admissions with positive 4AT and 594 (4.3%) with non-alert NEWS2 status. Sensitivity of NEWS2 for 4AT ≥4 was 17.8% (95% confidence interval (CI) 16.4--19.2), and specificity was 99.1% (95% CI 98.9--99.3). These findings suggest that NEWS2 in current practice has low sensitivity but high specificity for delirium. Further research is needed to improve routine inpatient monitoring for delirium. [ABSTRACT FROM AUTHOR]

The National Early Warning Score (NEWS), published in 2012, made no specific adjustments for older people. The updated NEWS2 (2017) incorporated new confusion as a category for consciousness. In this article, we consider the role of NEWS2 in detection of acute clinical deterioration in older people and how the score may be used to inform care, highlighting the additional aspects, such as care escalation decisions, that may ensue. We consider the evidence of NEWS and NEWS2 in assessment of the older person in different settings, including the potential benefits and limitations for care home residents. We suggest that NEWS2 may need adaptation for older people in future iterations, and that it should be used in conjunction with other clinical assessments, such as the Clinical Frailty Scale and the four 'A's test (4AT) for delirium. [ABSTRACT FROM AUTHOR]

Sporadic Alzheimer's disease (AD) is a neurodegenerative disorder that causes the most prevalent form of age-related dementia but its pathogenesis remains obscure. Altered regulation of metals, particularly pan-cerebral copper deficiency, and more regionally-localized perturbation of othermetals, are prominent in AD brain although data on how these CNS perturbations are reflected in the peripheral bloodstream are inconsistent to date. To assess the potential use of metal dysregulation to generate biomarkers in AD, we performed a case-control study of seven essential metals and selenium, measured by inductively coupled plasmamassspectrometry, in samples from AD and matched control cases. Metals were sodium, potassium, calcium, magnesium, iron, zinc, and copper. In the whole study-group and in female participants, plasma metal levels did not differ between cases and controls. In males by contrast, there was moderate evidence that zinc levels trended towards increase inAD[10.8 (10.2-11.5)] lmol/L, mean (± 95% CI; P = 0.021) compared with controls [10.2 (9.6-10.4)]. Thus alterations in plasma zinc levels differed between genders inAD. In correlational analysis, there was evidence for an increased number of 'strong' metal co-regulations in AD cases and differential comodulations of metal pairs: copper-sodium (Rcontrol- = - 0.03, RAD = 0.65; P = 0.009), and copper-calcium (Rcontrol = - 0.01, RAD = 0.65; P = 0.01) were significant in AD males, potentially consistent with reported evidence for dysregulation of copper in severely damaged brain regions in AD. In conclusion, our data suggest that the measurement of metals co-regulation in plasma may provide a useful representation of those metal perturbations taking place in the AD brain and therefore might be useful as plasma-based biomarkers. [ABSTRACT FROM AUTHOR]

The insertion allele in the gene encoding angiotensin-converting enzyme (ACE) is a risk factor for Alzheimer's disease (AD) and ACE is one of several peptidases that have the ability to degrade the neurotoxic amyloid-β peptide. ACE is a membrane-bound peptidase that is also present in a soluble form in plasma as a result of a zinc metalloprotease-mediated shedding event. Here we aimed to determine whether there is a difference in ACE in the plasma of late-onset clinically diagnosed AD patients (n = 94) as compared to age-matched non-demented control subjects (n = 188). Plasma ACE was lower in the AD subjects as compared to the controls both at baseline (p = 0.072) and after two years (p = 0.05). There was a greater reduction in plasma ACE in the AD subjects as compared to the control subjects over the two years. Plasma ACE did not correlate with cognitive function. The observed reduction in plasma ACE in AD may reflect a general decrease in the zinc metalloprotease-mediated shedding of a subset of membrane-bound proteins. [ABSTRACT FROM AUTHOR]

Background: Insulin-like growth factor (IGF)-1 has been implicated in the pathogenesis of Alzheimer's disease (AD).Methods: We compared the level of circulating total and bioavailable IGF-1, by simultaneous measurements of IGF-1 and IGF binding protein (IGFBP)-3, between 87 patients diagnosed with AD and 126 age and sex matched control subjects without cognitive impairment. Blood samples were collected and IGF-1 and IGFBP-3 measured by ELISA. Subjects were also genotyped for apolipoprotein E.Results: Total circulating IGF-1 levels were significantly raised in the AD group as compared to the control group (p=0.022). There was no significant difference in the circulating level of IGFBP-3 between the two groups. When the IGF-1 levels were ratioed against IGFBP-3 levels as an indicator of unbound, bioavailable circulating IGF-1, there was a significant increase in the molar IGF-1:IGFBP-3 ratio in the AD subjects (0.181 +/- 0.006) as compared to the controls (0.156 +/- 0.004) (p< 0.001). Logistic regression analysis revealed that an increase in the IGF-1:IGFBP-3 molar ratio increased the risk of AD significantly.Conclusion: The results of increased total and free circulating IGF-1 support the hypothesis that in its early stages late-onset AD reflects a state of resistance to IGF-1. [ABSTRACT FROM AUTHOR]

Frailty is a complex, age-related clinical condition that involves multiple contributing factors and raises the risk of adverse outcomes in older people. Given global population ageing trends, the growing prevalence and incidence of frailty pose significant challenges to health and social care systems in both high-income and lower-income countries. In this review, we highlight the disproportionate representation of research on frailty screening and management from high-income countries, despite how lower-income countries are projected to have a larger share of older people aged ≥60. However, more frailty research has been emerging from lower-income countries in recent years, paving the way for more context-specific guidelines and studies that validate frailty assessment tools and evaluate frailty interventions in the population. We then present further considerations for contextualising frailty in research and practice in lower-income countries. First, the heterogeneous manifestations of frailty call for research that reflects different geographies, populations, health systems, community settings and policy priorities; this can be driven by supportive collaborative systems between high-income and lower-income countries. Second, the global narrative around frailty and ageing needs re-evaluation, given the negative connotations linked with frailty and the introduction of intrinsic capacity by the World Health Organization as a measure of functional reserves throughout the life course. Finally, the social determinants of health as possible risk factors for frailty in lower-income countries and global majority populations, and potential socioeconomic threats of frailty to national economies warrant proactive frailty screening in these populations., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Delirium is common in hospitalised patients, and there is currently no specific treatment. Identifying and treating underlying somatic causes of delirium is the first priority once delirium is diagnosed. Several international guidelines provide clinicians with an evidence-based approach to screening, diagnosis and symptomatic treatment. However, current guidelines do not offer a structured approach to identification of underlying causes. A panel of 37 internationally recognised delirium experts from diverse medical backgrounds worked together in a modified Delphi approach via an online platform. Consensus was reached after five voting rounds. The final product of this project is a set of three delirium management algorithms (the Delirium Delphi Algorithms), one for ward patients, one for patients after cardiac surgery and one for patients in the intensive care unit., Competing Interests: DISCLOSURES The authors have no conflicts of interest to disclose.

Phenylketonuria (PKU) is a metabolic condition which, left untreated, results in severe and irreversible brain damage. Newborn screening and the development of the low phenylalanine (Phe) diet have transformed the outcomes for people with PKU. Those who have benefited from early treatment are now approaching their fifth and sixth decade. It is therefore timely to consider multi-morbidity in PKU and the effects of ageing, in parallel with the wider benefits of emerging treatment options in addition to dietary relaxation. We have conducted the first literature review of co-morbidity and ageing in the context of PKU. Avenues explored have emerged from limited study of multi-morbidity to date and the knowledge and critical enquiry of the authors. Findings suggest PKU to have a wider impact than brain development, and result in several intriguing questions that require investigation to attain the best outcomes for people with PKU in adulthood moving through to older age. We recognise the difficulty in studying longitudinal outcomes in rare diseases and emphasise the necessity to develop PKU registries and cohorts that facilitate well-designed studies to answer some of the questions raised in this review. Whilst awaiting new information in these areas we propose that clinicians engage with patients to make personalised and well-informed decisions around Phe control and assessment for co-morbidity., (© 2019 SSIEM.)

Unlabelled: Pathologic deposition of amyloid β (Aβ) protein is a key component in the pathogenesis of Alzheimer disease (AD) but not a feature of frontotemporal dementia (FTD). PET ligands for Aβ protein are increasingly used in diagnosis and research of dementia syndromes. Here, we report a PET study using (18)F-florbetapir in healthy controls and patients with AD and FTD., Methods: Ten healthy controls (mean age ± SD, 62.5 ± 5.2 y), 10 AD patients (mean age ± SD, 62.6 ± 4.5), and 8 FTD patients (mean age ± SD, 62.5 ± 9.6) were recruited to the study. All patients underwent detailed clinical and neuropsychologic assessment and T1-weighted MR imaging and were genotyped for apolipoprotein E status. All participants underwent dynamic (18)F-florbetapir PET on a high-resolution research tomograph, and FTD patients also underwent (18)F-FDG PET scans. Standardized uptake value ratios (SUVRs) were extracted for predefined gray and white matter regions of interest using cerebellar gray matter as a reference region. Static PET images were evaluated by trained raters masked to clinical status and regional analysis., Results: Total cortical gray matter (18)F-florbetapir uptake values were significantly higher in AD patients (median SUVR, 1.73) than FTD patients (SUVR, 1.13, P = 0.002) and controls (SUVR, 1.26, P = 0.04). (18)F-Florbetapir uptake was also higher in AD patients than FTD patients and controls in the frontal, parietal, occipital, and cingulate cortices and in the central subcortical regions. Only 1 FTD patient (homozygous for apolipoprotein E ε4) displayed high cortical (18)F-florbetapir retention, whereas (18)F-FDG PET demonstrated mesiofrontal hypometabolism consistent with the clinical diagnosis of FTD. Most visual raters classified 1 control (10%) and 8 AD (80%) and 2 FTD (25%) patients as amyloid-positive, whereas ratings were tied in another 2 FTD patients and 1 healthy control., Conclusion: Cortical (18)F-florbetapir uptake is low in most FTD patients, providing good discrimination from AD. However, visual rating of FTD scans was challenging, with a higher rate of discordance between interpreters than in AD and control subjects., (© 2015 by the Society of Nuclear Medicine and Molecular Imaging, Inc.)

Background: Alzheimer's disease (AD) is considered to be a disorder predominantly affecting memory. It is increasingly recognized that the cognitive profile may be heterogeneous. We hypothesized that it would be possible to define distinct “cognitive phenotypes” in older people with AD., Methods: Participants from three individual studies were included, consisting of 109 patients with a diagnosis of probable AD, and 91 age- and gender-matched control participants. All had demographic and cognitive assessment data available, including the Cambridge Cognitive Examination of the Elderly (CAMCOG). The CAMCOG scores and sub-scores were further analyzed using hierarchical cluster analysis and factor analysis., Results: Three clusters were identified. The scores loaded onto three factors representing the domains of attention, praxis, calculation, and perception; memory; and language comprehension and executive function. The main difference between the clusters related to degree of memory impairment. The composite score for memory between the clusters remained significantly different despite adjustment for illness duration and age of onset (p < 0.001)., Conclusions: These data suggest clinical heterogeneity within an older group of people with AD. This may have implications for diagnosis, prognosis, response to currently available treatments, and the development of novel therapies.

Alzheimer's disease (AD) is generally considered to be a disorder primarily affecting memory. It is increasingly recognized that the clinical presentation or "cognitive phenotype" is variable. The apolipoprotein E ε4 (APOE ε4) allele has been associated with an amnestic presentation, but does not appear to fully explain the high prevalence of family history within this group. We examined polymorphisms in the genes ACE and IDE in relation to cognitive phenotype. In this study 276 participants with AD were categorized into 1 of 4 cognitive phenotype classifications: typical, amnestic, language, and posterior. Family history and possession of the APOE ε4 allele were most prevalent in the amnestic group. Of the 10 genetic variants of IDE, and the 3 genetic variants of ACE studied, only ACErs4291 and ACErs1800764 were nominally associated with the amnestic presentation., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background: Tissue non-specific alkaline phosphatase (TNAP) has been shown to promote the neurotoxicity of extracellular tau which contributes to the spread of pathology in Alzheimer's disease (AD)., Objective: To investigate changes in TNAP activity in the hippocampus in both sporadic and familial AD, and to examine whether changes in neuronal TNAP are reflected systemically by looking at changes in plasma TNAP activity in AD., Methods: We measured the activity of TNAP in the hippocampus in sporadic AD, familial AD and appropriate age-matched controls, and in an ageing series (age: 25-88 years) of brains. In addition, we measured TNAP activity in plasma from 110 AD and 110 non-demented control participants., Results: TNAP activity was significantly increased in the hippocampus in sporadic (by 56%; p = 0.038) and familial AD (by 121%; p = 0.042) compared with the age-matched controls. However, there was no correlation of TNAP activity with age. Furthermore, plasma TNAP activity was increased in AD (by 13%; p = 0.018) and inversely correlated with cognitive function (r(s) = -0.211; p = 0.027)., Conclusion: Together, these data indicate that TNAP is increased in both sporadic and familial AD but not in the aged brain, indicating that the increase is likely a consequence of AD-associated changes in the brain. The neuronal change in TNAP is reflected in an increase in plasma TNAP in AD and is inversely correlated with cognitive function., (Copyright © 2011 S. Karger AG, Basel.)

We sought to identify new susceptibility loci for Alzheimer's disease through a staged association study (GERAD+) and by testing suggestive loci reported by the Alzheimer's Disease Genetic Consortium (ADGC) in a companion paper. We undertook a combined analysis of four genome-wide association datasets (stage 1) and identified ten newly associated variants with P ≤ 1 × 10(-5). We tested these variants for association in an independent sample (stage 2). Three SNPs at two loci replicated and showed evidence for association in a further sample (stage 3). Meta-analyses of all data provided compelling evidence that ABCA7 (rs3764650, meta P = 4.5 × 10(-17); including ADGC data, meta P = 5.0 × 10(-21)) and the MS4A gene cluster (rs610932, meta P = 1.8 × 10(-14); including ADGC data, meta P = 1.2 × 10(-16)) are new Alzheimer's disease susceptibility loci. We also found independent evidence for association for three loci reported by the ADGC, which, when combined, showed genome-wide significance: CD2AP (GERAD+, P = 8.0 × 10(-4); including ADGC data, meta P = 8.6 × 10(-9)), CD33 (GERAD+, P = 2.2 × 10(-4); including ADGC data, meta P = 1.6 × 10(-9)) and EPHA1 (GERAD+, P = 3.4 × 10(-4); including ADGC data, meta P = 6.0 × 10(-10)).

Alzheimer's disease (AD) is the most common form of dementia, with prevalence and the accompanying socioeconomic impact set to increase over the coming decades. Currently available medications result, at best, in modest cognitive improvement. With increasing understanding of the underlying pathology, new therapeutic targets are being identified at an ever-increasing rate. The key pathological events in the AD brain are deposition of insoluble amyloid-beta peptide (Abeta), formation of neurofibrillary tangles and neuroinflammation leading, ultimately, to neuronal cell death. Each of these will be considered, in detail, in terms of the variety of therapeutic approaches currently being investigated and mechanisms that may prove amenable to intervention in the future.

The accumulation of the amyloid-beta peptide, the main constituent of the "amyloid plaque", is widely considered to be the key pathological event in Alzheimer's disease. Amyloid-beta is produced from the amyloid precursor protein through the action of the proteases beta-secretase and gamma-secretase. Alternative cleavage of amyloid precursor protein by the enzyme alpha-secretase precludes amyloid-beta production. In addition, several proteases are involved in the degradation of amyloid-beta. This review focuses on the proteolytic mechanisms of amyloid-beta metabolism. An increasingly detailed understanding of proteolysis in both amyloid-beta deposition and clearance has identified some of these proteases as potential therapeutic targets for Alzheimer's disease. A more complex knowledge of these proteases takes us one step closer to developing "disease-modifying" therapies, but these advances also emphasize that significant challenges must be overcome before clinically effective drugs to treat Alzheimer's disease become a reality.