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Naomi Davey,1 Eimear Connolly,1 Paul Mc Elwaine,1,2 Sean P Kennelly1,2 1Department of Age Related Healthcare, Tallaght University Hospital, Dublin, Ireland; 2Department of Medical Gerontology, School of Medicine, Trinity College Dublin, Dublin, IrelandCorrespondence: Naomi Davey, Department of Age-Related Healthcare, Tallaght University Hospital, Dublin, Ireland, Email Naomi.davey@tuh.ieAbstract: This review article assesses the effectiveness and limitations of strategies to reduce falls among hospitalized older adults with frailty and dementia. It explores the efficacy of existing fall prevention strategies for a cohort that is acutely susceptible to falls and fall-related consequences. A systematic literature search was conducted across MEDLINE, Embase, CINAHL, and PsycINFO, employing Medical Subject Headings (MeSH) to identify studies on fall prevention strategies in hospitalized older adults with both dementia and frailty published from 2013 to 2023. The initial 643 records were distilled to eight articles, with Structured Interdisciplinary Bedside Rounds (SIBR) emerging as a notable intervention. SIBR demonstrated a reduction in falls by fostering improved interdisciplinary communication and care planning. However, a decline in family engagement during consecutive sessions suggests a need for strategies to sustain familial involvement. The findings advocate for patient-centered interventions that address the cognitive and functional challenges faced by this cohort of older adults. This review advocates for comprehensive and inclusive research in hospital environments to improve fall prevention strategies for frail older adults with dementia.Keywords: fall prevention, frailty, dementia, hospitalized older adults, interdisciplinary collaboration, patient-centered interventions

John J McCabe, Sean P KennellyDepartment of Age-Related Health Care, Tallaght Hospital, Dublin, IrelandAbstract: Older patients in the emergency department (ED) are a vulnerable population who are at a higher risk of functional decline and hospital reattendance subsequent to an ED visit, and have a high mortality rate in the months following an ED attendance. The delivery of acute care in a busy environment to this population presents its own unique challenge. The purpose of this review is to detail the common geriatric syndromes encountered in the ED as well as the appropriate strategies and instruments, which can be utilized to support the clinical decision matrix and improve outcomes.Keywords: delirium, dementia, emergency department, comprehensive geriatric assessment

Objectives: The advent of Disease Modifying Therapies (DMTs) for the treatment of Alzheimer's Disease (AD) has the potential to transform the lives of those with early AD. Timely identification of eligible patients is needed to ensure treatments are delivered during a narrow window of therapeutic opportunity. Appropriate clinical service design will hinge on improved understanding of future demands, thus there is a pressing need to investigate patient eligibility in real world clinical cohorts. The primary aim of this study is to assess the eligibility by appropriate use criteria (AUC) for lecanemab therapy in a real-world, undifferentiated clinical patient cohort attending a Regional Specialist Memory Clinic (RSMC), with the secondary aims of determining the proportion of patients with biomarker positive Alzheimer's Disease (AD) who would be eligible for lecanemab therapy by AUC. Clinical trial eligibility criteria were also applied to both groups and discrepancies that exist between eligibility rates explored., Methods: A retrospective cohort study of all new patients attending a RSMC from 1st January 2022 to 31st December 2022 was conducted. Data collected included demographic details, outcomes of diagnostic assessments and comorbidities. MRI images, where indicated, were reviewed. Amyloid positivity was defined as either Amyloid and Tau positive (A+T+) or Amyloid positive with a positive P-Tau/Ab42 ratio on cerebrospinal fluid (CSF) testing. Appropriate use criteria (AUC) and clinical trial criteria for lecanemab were applied. Proportion of eligible patients was calculated., Results: Eleven (5.9%) of 188 new patient attenders were eligible (average age 66.7 years [SD 8.9], 63.6% female) by AUC, with 26.2% of patients with biomarker positive Alzheimer's Disease eligible for lecanemab therapy. The most common reason for exclusion was a lack of biomarker confirmation of AD pathology followed by cognitive ineligibility (based on defined cognitive testing cut-offs) at the time of referral and/or initial assessment. Only 40.4% of patients had CSF testing for AD biomarkers while almost 20% of the patients with biomarker positive AD were excluded due to lack of a screening MRI in the previous 12 months., Conclusion: In this study, the potential eligibility rate by AUC of the entire patient cohort (5.9%) was limited by the small proportion of patients who had CSF testing for AD biomarkers. So while disease-modification with Lecanemab is a welcome therapeutic advance, although only a small proportion of people currently attending specialist services will be eligible. Successful delivery of DMTs will require significant resource allocation and optimisation of referral pathways to facilitate early identification of potentially eligible patients., (© 2024 The Author(s). International Journal of Geriatric Psychiatry published by John Wiley & Sons Ltd.)

People with intellectual disability are a vulnerable cohort who face challenges accessing health care. Compared with the general population, people with intellectual disability have an elevated risk of developing dementia, which often presents at a younger age and with atypical symptoms. The lifelong cognitive and functional difficulties faced by people with intellectual disability further complicate the diagnostic process. Specialised intellectual disability memory services and evaluation using reliable biomarkers of neurodegeneration are needed to improve diagnostic and prognostic certainty in this group. Inadequate specialist services and paucity of research on biomarkers in this population hinders progress and impedes the delivery of adequate health care. Although cerebrospinal fluid-based biomarkers and radiological biomarkers are used routinely in the evaluation of Alzheimer's disease in the general population, biological variation within the clinically heterogenous group of people with intellectual disability could affect the clinical utility of existing biomarkers. As disease-modifying therapies become available for the treatment of early Alzheimer's disease, and hopefully other neurodegenerative conditions in the future, biomarkers will serve as gatekeepers to establish the eligibility for such therapies. Inadequate representation of adults with intellectual disability in biomarker research will result in their exclusion from treatment with disease-modifying therapies, thus perpetuating the inequity in health care that is already faced by this group. The aim of this Series paper is to summarise current evidence on the application of biomarkers for Alzheimer's disease in a population with intellectual disability (that is not attributable to Down syndrome) and suspected cognitive decline., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: The effect of hearing and vision difficulties on the risk of developing dementia and worsening outcomes in people already living with dementia is well established. We evaluated the clinical impact of a hearing and vision rehabilitation and support programme on quality of life in people with mild-to-moderate dementia and concurrent sensory difficulties., Methods: We conducted a parallel-group, multicentre, observer-blind, superiority randomised controlled trial in seven older adult clinics in five European countries (Cyprus, France, Greece, Ireland, and the UK). People with mild-to-moderate dementia with adult-acquired hearing difficulties, vision difficulties, or both were randomly assigned (1:1) along with their care partner to an 18-week home-basedsensory support intervention (SSI) of tailored hearing and vision rehabilitation and support, or to care as usual. Randomisation was blocked (block size of four, six, or eight) and stratified by country, with allocation assigned via a remote web-based system. The SSI included: full hearing assessment, vision assessment, or both; fitting of hearing aids, glasses, or other sensory aids; and home-based support from a sensory support therapist to assist adherence and uptake of sensory aids, foster social networking, and optimise the home sensory environment. Care as usual involved no additional intervention beyond services normally available to people with dementia at the respective sites. The primary outcome was health-related quality of life (Dementia Quality of Life Instrument [DEMQoL]) score at 36 weeks, reported as an adjusted mean difference. Analyses were done according to the intention-to-treat principle. This trial is registered with the ISRCTN Registry, ISRCTN17056211., Findings: Between May 4, 2018, and May 6, 2021, 252 people with mild-to-moderate dementia were randomly assigned, of whom 251 (n=126 in the SSI group and n=125 in the care as usual group) were included in the analysis. The mean age of participants was 79·6 years (SD 5·8), and 132 (53%) were women. After a median follow-up time of 37·7 weeks (IQR 36·2-39·0), the mean DEMQoL score was 92·8 (SD 15·2) in the SSI group and 92·8 (14·0) in the care as usual group (adjusted difference 0·18, 95% CI -2·13 to 2·30, p=0·87). Among 114 adverse events reported for 56 (44%) participants in the SSI group, ten events in nine participants were related or possibly related to the intervention (medical device pain or discomfort n=6, ear pain n=1, scratch to the ear n=1, sore eye n=1, redness n=1; all of grade 1). Serious adverse events were reported for 25 (20%) participants in the SSI group and 16 (13%) in the care as usual group. Six (5%) participants in the SSI group and five (4%) in the care as usual group died. None of the serious adverse events or deaths were related to the study intervention or procedures., Interpretation: This study showed no improvement in quality in life in participants who received the intervention in the longer term. Sensory difficulties are common in people with dementia and interventions aimed at improving sensory-cognitive health should be explored further., Funding: EU Horizon 2020., Competing Interests: Declaration of interests IL declares membership of advisory boards for Biogen, NovoNordisk, and Eisai; honorarium for a lecture and support for attending meetings or travel from Biogen; and membership of the Board of Directors for Lewy Body Ireland (unpaid, charity). CJA and PD were supported by the National Institute for Health and Care Research (NIHR) Manchester Biomedical Research Centre under grant BRC-1215-20007. All other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Midlife cardiovascular risk factors such as Type 2 Diabetes (T2DM) and obesity are associated with the later development of cognitive impairment and dementia. Systemic inflammation is postulated as a crucial mechanism, yet there are few studies examining this at the earliest stages prior to overt cognitive impairment. To assess this, we recruited a cohort of middle-aged cognitively-unimpaired individuals with and without uncomplicated T2DM. Comprehensive neuropsychological assessment was performed at baseline and at 4-year follow-up. Ten serum chemokines and cytokines (Eotaxin, MCP-1, MIP-1β, CXCL10, IL-6, IL-10, IL12p70, IL-17A, IFN-γ and TNF-α) were measured at both baseline and follow-up using high-sensitivity assays. Overall, 136 participants were recruited including 90 with uncomplicated midlife T2DM (age 52.6 ± 8.3; 47% female) and 46 without (age 52.9 ± 8.03; 61% female). Cognitive trajectories were stable over time and did not differ with T2DM. Yet on cross-sectional analyses at both baseline and follow-up, greater circulating IL-17A was consistently associated with poorer performance on tests of executive function/attention (β: 0.21; -0.40, -0.02, p = 0.03 at baseline; β: 0.26; -0.46, -0.05, p = 0.02 at follow-up). Associations persisted on covariate adjustment and did not differ by T2DM status. In summary, we provide evidence that greater circulating IL-17A levels were associated with poorer executive function in midlife, independent of T2DM. Long-term follow-up of this and other cohorts will further elucidate the earliest stages in the relationship between systemic inflammation and cognitive decline to provide further mechanistic insights and potentially identify those at greatest risk for later cognitive decline., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Sean P. Kennelly reports financial support was provided by 10.13039/501100004162Meath Foundation. Adam H. Dyer reports financial support was provided by 10.13039/100010269Wellcome Trust. Adam H. Dyer reports financial support was provided by Health Research Board. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 Published by Elsevier Inc.)

Gait speed is increasingly recognized as an important health indicator. However, gait analysis in clinical settings often encounters inconsistencies due to methodological variability and resource constraints. To address these challenges, GaitKeeper uses artificial intelligence (AI) and augmented reality (AR) to standardize gait speed assessments. In laboratory conditions, GaitKeeper demonstrates close alignment with the Vicon system and, in clinical environments, it strongly correlates with the Gaitrite system. The integration of a cloud-based processing platform and robust data security positions GaitKeeper as an accurate, cost-effective, and user-friendly tool for gait assessment in diverse clinical settings.

Background: Medications with sedative or anticholinergic properties should be prescribed with caution in those with cognitive complaints. This is particularly relevant in people ageing with an intellectual disability (ID). Higher drug burden index (DBI) scores are associated with increased frailty and falls and reduced quality of life in older people and increased risk of adverse effects (daytime somnolence, constipation) in those with ID. While previous studies have shown that the ID population has higher rates of drug burden and a higher propensity to be prescribed an antipsychotic than the general population, the degree of burden has not been assessed specifically in those with ID and cognitive complaints., Methods: We assessed drug burden in a cohort of sequential referrals to a national memory service for people with ID. All patients were referred for assessment of cognitive complaints (self-reported or caregiver-reported problems with memory or cognition). DBI was calculated individually for each participant, and the impact of aetiology of ID, level of ID, age, psychiatric/neurological comorbidities and diagnostic outcome on DBI scores was assessed., Results: The study population was 58.6% female with a median age of 55 years and aetiology of ID was Down syndrome (DS) in 71.3%. Consensus diagnosis was Alzheimer's dementia in 40.2%, mild cognitive impairment in 29.9% and cognitively unimpaired from baseline in 25.3%. Medication use was high with 95.4% taking medications, with a median number of medications of 4 (interquartile range 4) and a rate of polypharmacy (≥5 medications) of 51.7%. Overall, 65.5% were exposed to sedative or anticholinergic medications with 39.1% exposed to a clinically significant DBI score >1. Those with psychiatric comorbidities, non-DS aetiology or epilepsy were significantly more likely to have a DBI score >1., Conclusions: People with ID and incipient cognitive complaints have a high level of drug burden, which concerningly exceeds that of the general population., (© 2024 John Wiley & Sons and MENCAP.)

Background: Plasma p-tau217 has emerged as the most promising blood-based marker (BBM) for the detection of Alzheimer Disease (AD) pathology, yet few studies have evaluated plasma p-tau217 performance in memory clinic settings. We examined the performance of plasma p-tau217 for the detection of AD using a high-sensitivity immunoassay in individuals undergoing diagnostic lumbar puncture (LP)., Methods: Paired plasma and cerebrospinal fluid (CSF) samples were analysed from the TIMC-BRAiN cohort. Amyloid (Aβ) and Tau (T) pathology were classified based on established cut-offs for CSF Aβ 42 and CSF p-tau181 respectively. High-sensitivity electrochemiluminescence (ECL) immunoassays were performed on paired plasma/CSF samples for p-tau217, p-tau181, Glial Fibrillary Acidic Protein (GFAP), Neurofilament Light (NfL) and total tau (t-tau). Biomarker performance was evaluated using Receiver-Operating Curve (ROC) and Area-Under-the-Curve (AUC) analysis., Results: Of 108 participants (age: 69 ± 6.5 years; 54.6% female) with paired samples obtained at time of LP, 64.8% (n = 70/108) had Aβ pathology detected (35 with Mild Cognitive Impairment and 35 with mild dementia). Plasma p-tau217 was over three-fold higher in Aβ + (12.4 pg/mL; 7.3-19.2 pg/mL) vs. Aβ- participants (3.7 pg/mL; 2.8-4.1 pg/mL; Mann-Whitney U = 230, p < 0.001). Plasma p-tau217 exhibited excellent performance for the detection of Aβ pathology (AUC: 0.91; 95% Confidence Interval [95% CI]: 0.86-0.97)-greater than for T pathology (AUC: 0.83; 95% CI: 0.75-0.90; z = 1.75, p = 0.04). Plasma p-tau217 outperformed plasma p-tau181 for the detection of Aβ pathology (z = 3.24, p < 0.001). Of the other BBMs, only plasma GFAP significantly differed by Aβ status which significantly correlated with plasma p-tau217 in Aβ + (but not in Aβ-) individuals. Application of a two-point threshold at 95% and 97.5% sensitivities & specificities may have enabled avoidance of LP in 58-68% of cases., Conclusions: Plasma p-tau217 measured using a high-sensitivity ECL immunoassay demonstrated excellent performance for detection of Aβ pathology in a real-world memory clinic cohort. Moving forward, clinical use of plasma p-tau217 to detect AD pathology may substantially reduce need for confirmatory diagnostic testing for AD pathology with diagnostic LP in specialist memory services., (© 2024. The Author(s).)

Midlife risk factors such as type 2 diabetes mellitus (T2DM) confer a significantly increased risk of cognitive impairment in later life with executive function, memory, and attention domains often affected first. Spatiotemporal gait characteristics are emerging as important integrative biomarkers of neurocognitive function and of later dementia risk. We examined 24 spatiotemporal gait parameters across five domains of gait previously linked to cognitive function on usual-pace, maximal-pace, and cognitive dual-task gait conditions in 102 middle-aged adults with (57.5 ± 8.0 years; 40% female) and without (57.0 ± 8.3 years; 62.1% female) T2DM. Neurocognitive function was measured using a neuropsychological assessment battery. T2DM was associated with significant changes in gait phases and rhythm domains at usual pace, and greater gait variability observed during maximal pace and dual tasks. In the overall cohort, both the gait pace and rhythm domains were associated with memory and executive function during usual pace. At maximal pace, gait pace parameters were associated with reaction time and delayed memory. During the cognitive dual task, associations between gait variability and both delayed memory/executive function were observed. Associations persisted following covariate adjustment and did not differ by T2DM status. Principal components analysis identified a consistent association of slower gait pace (step/stride length) and increased gait variability during maximal-pace walking with poorer memory and executive function performance. These data support the use of spatiotemporal gait as an integrative biomarker of neurocognitive function in otherwise healthy middle-aged individuals and reveal discrete associations between both differing gait tasks and gait domains with domain-specific neuropsychological performance. Employing both maximal-pace and dual-task paradigms may be important in cognitively unimpaired populations with risk factors for later cognitive decline-with the aim of identifying individuals who may benefit from potential preventative interventions.

Background: Introducing new disease-modifying therapies (DMTs) for Alzheimer's disease demands a fundamental shift in diagnosis and care for most health systems around the world. Understanding the views of health professionals, potential patients, care partners and taxpayers is crucial for service planning and expectation management about these new therapies., Aims: To investigate the public's and professionals' perspectives regarding (1) acceptability of new DMTs for Alzheimer's disease; (2) perceptions of risk/benefits; (3) the public's willingness to pay (WTP)., Method: Informed by the 'theoretical framework of acceptability', we conducted two online surveys with 1000 members of the general public and 77 health professionals in Ireland. Descriptive and multivariate regression analyses examined factors associated with DMT acceptance and WTP., Results: Healthcare professionals had a higher acceptance (65%) than the general public (48%). Professionals were more concerned about potential brain bleeds (70%) and efficacy (68%), while the public focused on accessibility and costs. Younger participants (18-24 years) displayed a higher WTP. Education and insurance affected WTP decisions., Conclusions: This study exposes complex attitudes toward emerging DMTs for Alzheimer's disease, challenging conventional wisdom in multiple dimensions. A surprising 25% of the public expressed aversion to these new treatments, despite society's deep-rooted fear of dementia in older age. Healthcare professionals displayed nuanced concerns, prioritising clinical effectiveness and potential brain complications. Intriguingly, younger, better-educated and privately insured individuals exhibited a greater WTP, foregrounding critical questions about healthcare equity. These multifaceted findings serve as a guidepost for healthcare strategists, policymakers and ethicists as we edge closer to integrating DMTs into Alzheimer's disease care.

Introduction: Problematic polypharmacy is the prescribing of five or more medications potentially inappropriately. Unintentional prescribing cascades represent an under-researched aspect of problematic polypharmacy and occur when an adverse drug reaction (ADR) is misinterpreted as a new symptom resulting in the initiation of a new medication. The aim of this study was to elicit key stakeholders' perceptions of and attitudes towards problematic polypharmacy, with a focus on prescribing cascades., Methods: qualitative one-to-one semi-structured interviews were conducted with predefined key stakeholder groups. Inductive thematic analysis was employed., Results: Thirty-one stakeholders were interviewed: six patients, two carers, seven general practitioners, eight pharmacists, four hospital doctors, two professional organisation representatives and two policymakers. Three main themes were identified: (i) ADRs and prescribing cascades-a necessary evil. Healthcare professionals (HCPs) expressed concern that experiencing an ADR would negatively impact patients' confidence in their doctor. However, patients viewed ADRs pragmatically as an unpredictable risk. (ii) Balancing the risk/benefit tipping point. The complexity of prescribing decisions in the context of polypharmacy made balancing this tipping point challenging. Consequently, HCPs avoided medication changes. (iii) The minefield of medication reconciliation. Stakeholders, including patients and carers, viewed medication reconciliation as a perilous activity due to systemic communication deficits., Conclusion: Stakeholders believed that at a certain depth of polypharmacy, the risk that a new symptom is being caused by an existing medication becomes incalculable. Therefore, in the absence of harm, medication changes were avoided. However, medication reconciliation post hospital discharge compelled prescribing decisions and was seen as a high-risk activity by stakeholders., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Geriatrics Society.)

Purpose: Antipsychotic use in Alzheimer disease (AD) is associated with adverse events and mortality. Whilst postulated to cause/exacerbate orthostatic hypotension (OH), the exact relationship between antipsychotic use and OH has never been explored in AD-a group who are particularly vulnerable to neuro-cardiovascular instability and adverse effects of medication on orthostatic blood pressure (BP) behaviour., Methods: We analysed longitudinal data from an 18-month trial of Nilvadipine in mild-moderate AD. We assessed the effect of long-term antipsychotic use (for the entire 18-month study duration) on orthostatic BP phenotypes measured on eight occasions, in addition to the relationship between antipsychotic use, BP phenotypes and incident falls., Results: Of 509 older adults with AD (aged 72.9 ± 8.3 years, 61.9% female), 10.6% (n = 54) were prescribed a long-term antipsychotic. Over 18 months, long-term antipsychotic use was associated with a greater likelihood of experiencing sit-to-stand OH (ssOH) (OR: 1.21; 1.05-1.38, p = 0.009) which persisted on covariate adjustment. Following adjustment for important clinical confounders, both antipsychotic use (IRR: 1.80, 1.11-2.92, p = 0.018) and ssOH (IRR: 1.44, 1.00-2.06, p = 0.048) were associated with a greater risk of falls/syncope over 18 months in older adults with mild-moderate AD., Conclusion: Even in mild-to-moderate AD, long-term antipsychotic use was associated with ssOH. Both antipsychotic use and ssOH were associated with a greater risk of incident falls/syncope over 18 months. Further attention to optimal prescribing interventions in this cohort is warranted and may involve screening older adults with AD prescribed antipsychotics for both orthostatic symptoms and falls., (© 2024. The Author(s), under exclusive licence to European Geriatric Medicine Society.)

Alzheimer's Disease (ad) is the most common cause of dementia, and in addition to cognitive decline, it directly contributes to physical frailty, falls, incontinence, institutionalisation and polypharmacy in older adults. Increasing availability of clinically validated biomarkers including cerebrospinal fluid and positron emission tomography to assess both amyloid and tau pathology has led to a reconceptualisation of ad as a clinical-biological diagnosis, rather than one based purely on clinical phenotype. However, co-pathology is frequent in older adults which influence the accuracy of biomarker interpretation. Importantly, some older adults with positive amyloid or tau pathological biomarkers may never experience cognitive impairment or dementia. These strides towards achieving an accurate clinical-biological diagnosis are occurring alongside recent positive phase 3 trial results reporting statistically significant effects of anti-amyloid Disease-Modifying Therapies (DMTs) on disease severity in early ad. However, the real-world clinical benefit of these DMTs is not clear and concerns remain regarding how trial results will translate to real-world clinical populations, potential adverse effects (including amyloid-related imaging abnormalities), which can be severe and healthcare systems readiness to afford and deliver potential DMTs to appropriate populations. Here, we review recent advances in both clinical-biological diagnostic classification and future treatment in older adults living with ad. Advocating for access to both more accurate clinical-biological diagnosis and potential DMTs must be done so in a holistic and gerontologically attuned fashion, with geriatricians advocating for enhanced multi-component and multi-disciplinary care for all older adults with ad. This includes those across the ad severity spectrum including older adults potentially ineligible for emerging DMTs., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Geriatrics Society.)

Introduction: Alzheimer's disease and other dementias affect >50 million individuals globally and are characterised by broad clinical and biological heterogeneity. Cohort and biobank studies have played a critical role in advancing the understanding of disease pathophysiology and in identifying novel diagnostic and treatment approaches. However, further discovery and validation cohorts are required to clarify the real-world utility of new biomarkers, facilitate research into the development of novel therapies and advance our understanding of the clinical heterogeneity and pathobiology of neurodegenerative diseases., Methods and Analysis: The Tallaght University Hospital Institute for Memory and Cognition Biobank for Research in Ageing and Neurodegeneration (TIMC-BRAiN) will recruit 1000 individuals over 5 years. Participants, who are undergoing diagnostic workup in the TIMC Memory Assessment and Support Service (TIMC-MASS), will opt to donate clinical data and biological samples to a biobank. All participants will complete a detailed clinical, neuropsychological and dementia severity assessment (including Addenbrooke's Cognitive Assessment, Repeatable Battery for Assessment of Neuropsychological Status, Clinical Dementia Rating Scale). Participants undergoing venepuncture/lumbar puncture as part of the clinical workup will be offered the opportunity to donate additional blood (serum/plasma/whole blood) and cerebrospinal fluid samples for longitudinal storage in the TIMC-BRAiN biobank. Participants are followed at 18-month intervals for repeat clinical and cognitive assessments. Anonymised clinical data and biological samples will be stored securely in a central repository and used to facilitate future studies concerned with advancing the diagnosis and treatment of neurodegenerative diseases., Ethics and Dissemination: Ethical approval has been granted by the St. James's Hospital/Tallaght University Hospital Joint Research Ethics Committee (Project ID: 2159), which operates in compliance with the European Communities (Clinical Trials on Medicinal Products for Human Use) Regulations 2004 and ICH Good Clinical Practice Guidelines. Findings using TIMC-BRAiN will be published in a timely and open-access fashion., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.)

Context: The assessment of decision-making ability of older adults with cognitive impairment is a complex challenge that geriatricians often face in relation to risk-taking situations (driving, aging in place, financial decisions, etc.). However, there are no clear and consensual practice guidelines. An overview of current practices and needs seemed necessary., Methods: We co-created and conducted an online survey to describe practice and knowledge, among European geriatricians. The survey was structured in 3 parts: a description of the professional's practice regarding cognitive impairment, a specific questionnaire about everyday risky decision-making evaluation and an investigation of the clinician's knowledge about relevant ethical and legal recommendations. Each part consisted of both multiple choice and open questions, analyzed through descriptive statistics and qualitative analysis methods., Results: Based on the responses of 123 geriatricians across Europe, our survey showed that clinical interview is the cornerstone of geriatric assessment of decision-making ability of patients with mild to moderate dementia. When faced with risk-taking dilemma situations, geriatricians tend to favor a context of safety above autonomy, but they can support risky decision-making if it is consistent with the patient's previous lifestyle, depending on the degree of risk to self and others, on the decision-making ability assessed, and if there is some form of shared decision-making., Conclusion: Assessing decision-making ability is challenging for geriatricians, who in our study relied more on their clinical interview and global cognitive tests than more in-depth evaluations. Supporting independent decision-making, when associated with risk-taking, requires better detection and anticipation shared with the patient environment., (© 2023. The Author(s), under exclusive licence to European Geriatric Medicine Society.)

Modifiable risk factors for dementia remain prevalent in Ireland. A detailed examination of barriers to risk reduction behaviours in an Irish context has heretofore been lacking. Many existing studies examining barriers to brain health behaviours fail to examine how they might vary across different modifiable risk factors. This study undertook a detailed assessment of barriers to individual risk reduction behaviours. As existing research suggests that barriers may vary across sociodemographic factors, we sought to investigate the distribution of barriers across age, gender, educational status, and household income. The Five Lives Brain Health Ireland Survey is a cross-sectional survey that was distributed online amongst a non-patient population. The survey captured the following: (1) Sociodemographic factors; (2) Barriers to brain health behaviours; (3) Exposure to, and knowledge of, modifiable risk factors for dementia, namely diet, social interaction, exercise, hypertension, sleep, current low mood/depression, current smoking, alcohol consumption, cognitive stimulation, hearing impairment, diabetes, air pollution, and head injury; (4) Participants' perceptions regarding potential for dementia prevention, and risk reduction. Lack of motivation was the most prevalent barrier to consuming a healthy diet (64%, n  = 213), physical activity (77.7%, n  = 167), smoking cessation (68%, n  = 85), and moderation of alcohol intake (56.3%, n  = 67). Practical factors were the most prevalent barriers to addressing low mood (56.5%, n  = 87), air pollution (30.1%, n  = 58), hearing impairment (63.8%, n  = 44), diabetes (11.1%, n  = 5), and head injury (80%, n  = 8). Emotional factors were the most prevalent barriers to engaging in mentally stimulating activity (56.9%, n  = 66), social activity (54.9%, n  = 302), and good sleep (70.1%, n = 129). Lack of knowledge was the most prevalent barrier to hypertension control (14.4%, n = 29). Distribution of barriers varied across age, gender, educational status, and household income. This study investigated barriers to lifestyle change to improve brain health in an Irish sample of adults aged 50 and above. Detailed subtyping of barriers, as well as examination of differences according to age, gender, education, and income were undertaken. The heterogeneity of barriers to brain health behaviours revealed in this study highlights the necessity to tailor public health interventions to their target population, taking into account the gender, age, educational status, and income of recipients., Competing Interests: This study received funding from Five Lives SAS/SharpTx Ltd., who sponsored performance of the survey. EGL and KM were previously employed by Five Lives SAS/SharpTx Ltd. LJ and PV are currently employed by Five Lives. IK is a paid medical advisor of Five Lives SAS/SharpTx Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Dukelow, Vassilev, Lawrence, Jacobson, Koychev, Muhammed and Kennelly.)

Background: Over 55 million adults are living with dementia globally, which is projected to reach 157 million by 2050. Mild cognitive impairment (MCI), a syndrome of memory impairment with intact activities of daily living, may precede dementia by several years. Around 5-15% of individuals with MCI convert to dementia annually. Novel treatments which delay progression of MCI to dementia are urgently needed. Transcutaneous vagal nerve stimulation (tVNS) is a non-invasive neuromodulation technique that targets the vagus nerve. Importantly, tVNS has been shown to improve cognition in healthy volunteers, but has not been extensively examined as a potential therapeutic approach in MCI. VINCI-AD will examine the safety and feasibility of tVNS in older adults with MCI., Design: VINCI-AD is an investigator-led, single-site, single-blind, sham-controlled crossover pilot study which aims to assess the safety and feasibility of tVNS in 40 participants with amnestic MCI. All participants will attend for three consecutive study visits during which they will be randomised to receive no stimulation (baseline), active tVNS stimulation (stimulation at cymba conchae of left ear) or sham tVNS stimulation (at earlobe). Safety will be primarily assessed by ascertainment of adverse events. Further safety assessment will examine the impact of acute tVNS on subjective (orthostatic symptoms), peripheral (finometry-based blood pressure) and central (assessed via Near Infrared Spectroscopy [NIRS]) haemodynamic responses to active stand. Feasibility will be determined using a custom-designed occupational assessment of device usability. Exploratory secondary analysis in VINCI-AD will examine the potential impact of acute tVNS on associative memory, spatial memory and inhibitory control to inform sample size estimates for future trials of tVNS in older adults with MCI., Discussion: VINCI-AD will report on the safety (adverse events/haemodynamic responses to active stand) and feasibility of tVNS as a potential therapeutic option in MCI. Detailed reporting of study eligibility and completion rates will be reported. Exploratory analysis will examine the potential cognitive benefits of acute tVNS on cognitive function in MCI to report potential effect sizes that may inform future clinical trials in this cohort., Trial Registration: https://clinicaltrials.gov/ct2/show/NCT05514756 . Trial Registration Number NCT05514756 (24th August 2022 for this protocol, version 1.0.)., (© 2023. The Author(s).)

Apathy is a complex multi-dimensional syndrome that affects up to 70% of individuals with Alzheimer's disease (AD). Whilst many frameworks to define apathy in AD exist, most include loss of motivation or goal-directed behaviour as the central feature. Apathy is associated with significant impact on persons living with AD and their caregivers and is also associated with accelerated cognitive decline across the AD spectrum. Neuroimaging studies have highlighted a key role of fronto-striatial circuitry including the anterior cingulate cortex (ACC), orbito-frontal cortex (OFC) and associated subcortical structures. Importantly, the presence and severity of apathy strongly correlates with AD stage and neuropathological biomarkers of amyloid and tau pathology. Following from neurochemistry studies demonstrating a central role of biogenic amine neurotransmission in apathy syndrome in AD, recent clinical trial data suggest that apathy symptoms may improve following treatment with agents such as methylphenidate-which may have an important role alongside emerging non-pharmacological treatment strategies. Here, we review the diagnostic criteria, rating scales, prevalence, and risk factors for apathy in AD. The underlying neurobiology, neuropsychology and associated neuroimaging findings are reviewed in detail. Finally, we discuss current treatment approaches and strategies aimed at targeting apathy syndrome in AD, highlighting areas for future research and clinical trials in patient cohorts.

Cognitive decline in Alzheimer's disease correlates with the extent of tau pathology, in particular tau hyperphosphorylation that initially appears in the transentorhinal and related regions of the brain including the hippocampus. Recent evidence indicates that tau hyperphosphorylation caused by either amyloid-β or long-term depression, a form of synaptic weakening involved in learning and memory, share similar mechanisms. Studies from our group and others demonstrate that long-term depression-inducing low-frequency stimulation triggers tau phosphorylation at different residues in the hippocampus under different experimental conditions including aging. Conversely, certain forms of long-term depression at hippocampal glutamatergic synapses require endogenous tau, in particular, phosphorylation at residue Ser396. Elucidating the exact mechanisms of interaction between tau and long-term depression may help our understanding of the physiological and pathological functions of tau/tau (hyper)phosphorylation. We first summarize experimental evidence regarding tau-long-term depression interactions, followed by a discussion of possible mechanisms by which this interplay may influence the pathogenesis of Alzheimer's disease. Finally, we conclude with some thoughts and perspectives on future research about these interactions., Competing Interests: None

Background: In addition to the clear cardiovascular benefit, there has been renewed interest in the potential of statins in the prevention of cognitive impairment and dementia in older adults. However, whether ongoing statin use can delay cognitive decline or dementia progression in those with established Alzheimer dementia, is unclear., Methods: Using data from NILVAD, we analysed the association between ongoing statin use and cognitive decline (Alzheimer Disease Assessment Scale-Cognitive Subsection [ADAS-Cog])/dementia progression (Clinical Dementia Rating Scale [CDR-Sb]/Disability Assessment for Dementia [DAD]) over 18 months in older adults with mild-moderate AD. Additionally, we assessed the association between ongoing statin use and adverse events in mild-moderate AD., Results: Over one-third (34.9%) of 510 older adults with mild-moderate AD (aged: 72.9 years; 61.9% female) used a statin for the 18-month study duration. Statin use was not associated with the rate of cognitive decline (β: -0.67; 95% CI: -1.71, 0.36, p = 0.20) or dementia progression (β: -0.34; 95% CI -0.71, 0.02; p = 0.07 for CDR-Sb/ β: -2.00; -5.70, 1.70; p = 0.29 for DAD). Further, ongoing statin use was not associated with adverse events, serious adverse events, unscheduled GP visits, or unscheduled hospitalisation., Conclusion: Ongoing statin use was not associated with cognitive decline or dementia progression in mild-moderate AD. Similarly, use was not associated with adverse events including abnormal liver function tests or falls. Whilst safe in those with AD, the current results suggest ongoing statin use does not delay cognitive decline or clinical progression in established AD., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Murphy et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Aims: Type 2 diabetes is a risk factor for late-life dementia, but dementia prevention strategies have yet to be comprehensively evaluated in people with diabetes. The Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) demonstrated cognitive benefits of a 2-year multidomain lifestyle intervention. However, given the intensive nature of FINGER, there is uncertainty about whether it can be implemented in other high-risk populations. Our aim was to explore attitudes towards dementia risk, and barriers to an intervention based on the FINGER model in older adults with type 2 diabetes living in rural areas of Ireland., Methods: Focus groups were conducted with 21 adults (11 men and 10 women) aged 60+ years with type 2 diabetes living in border regions of north and south Ireland. Data were analysed using thematic analysis., Results: There was limited understanding of diabetes as a risk factor for late-life dementia. The main barriers to engagement with the multidomain intervention were eating foods that were not compatible with cultural norms, time and travel constraints, and perceived lack of self-efficacy and self-motivation for adopting the desired diet, exercise and computerised cognitive training (CCT) behaviours. Facilitators for intervention acceptability included the provision of culturally tailored and personalised education, support from a trusted source, and inclusion of goal setting and self-monitoring behavioural strategies., Conclusions: While there was high acceptability for a brain health intervention, several barriers including cultural food norms and low self-efficacy for adopting the diet, exercise and CCT components would need to be considered in the intervention design. Findings from this study will be used to inform local decisions regarding the adaptation of FINGER for people with type 2 diabetes. The feasibility of the adapted multidomain intervention will then be evaluated in a future pilot trial., (© 2022 The Authors. Diabetic Medicine published by John Wiley & Sons Ltd on behalf of Diabetes UK.)

Clinical outcomes from infection with SARS-CoV-2, the cause of the COVID-19 pandemic, are remarkably variable ranging from asymptomatic infection to severe pneumonia and death. One of the key drivers of this variability is differing trajectories in the immune response to SARS-CoV-2 infection. Many studies have noted markedly elevated cytokine levels in severe COVID-19, although results vary by cohort, cytokine studied and sensitivity of assay used. We assessed the immune response in acute COVID-19 by measuring 20 inflammatory markers in 118 unvaccinated patients with acute COVID-19 (median age: 70, IQR: 58-79 years; 48.3% female) recruited during the first year of the pandemic and 44 SARS-CoV-2 naïve healthy controls. Acute COVID-19 was associated with marked elevations in nearly all pro-inflammatory markers, whilst eleven markers (namely IL-1β, IL-2, IL-6, IL-10, IL-18, IL-23, IL-33, TNF-α, IP-10, G-CSF and YKL-40) were associated with disease severity. We observed significant correlations between nearly all markers elevated in those infected with SARS-CoV-2 consistent with widespread immune dysregulation. Principal component analysis highlighted a pro-inflammatory cytokine signature (with strongest contributions from IL-1β, IL-2, IL-6, IL-10, IL-33, G-CSF, TNF-α and IP-10) which was independently associated with severe COVID-19 (aOR: 1.40, 1.11-1.76, p=0.005), invasive mechanical ventilation (aOR: 1.61, 1.19-2.20, p=0.001) and mortality (aOR 1.57, 1.06-2.32, p = 0.02). Our findings demonstrate elevated cytokines and widespread immune dysregulation in severe COVID-19, adding further evidence for the role of a pro-inflammatory cytokine signature in severe and critical COVID-19., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Hawerkamp, Dyer, Patil, McElheron, O’Dowd, O’Doherty, Mhaonaigh, George, O’Halloran, Reddy, Kenny, Little, Martin-Loeches, Bergin, Kennelly, Donnelly, Bourke, Long, Sui, Doherty, Conlon, Cheallaigh and Fallon.)

Background: Orthostatic hypotension (OH), cognitive impairment (Cog) and mobility impairment (MI) frequently co-occur in older adults who fall. This study examines clustering of these three geriatric syndromes and ascertains their relationship with future falls/fractures in a large cohort of community-dwelling people ≥ 65 years during 8-year follow-up., Methods: OH was defined as an orthostatic drop ≥ 20 mmHg in systolic blood pressure (from seated to standing) and/or reporting orthostatic unsteadiness. CI was defined as Mini Mental State Examination ≤ 24 and/or self-reporting memory as fair/poor. MI was defined as Timed Up and Go ≥12 s. Logistic regression models, including three-way interactions, assessed the longitudinal association with future falls (explained and unexplained) and fractures., Results: Almost 10% (88/2,108) of participants had all three Bermuda syndromes. One-fifth of participants had an unexplained fall during follow-up, whereas 1/10 had a fracture. There was a graded relationship with incident unexplained falls and fracture as the number of Bermuda syndromes accumulated. In fully adjusted models, the cluster of OH, CI and MI was most strongly associated with unexplained falls (odds ratios (OR) 4.33 (2.59-7.24); P < 0.001) and incident fracture (OR 2.51 (1.26-4.98); P = 0.045). Other clusters significantly associated with unexplained falls included OH; CI and MI; MI and OH; CI and OH. No other clusters were associated with fracture., Discussion: The 'Bermuda Triangle' of OH, CI and MI was independently associated with future unexplained falls and fractures amongst community-dwelling older people. This simple risk identification scheme may represent an ideal target for multifaceted falls prevention strategies in community-dwelling older adults., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Geriatrics Society. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Up to 40% of dementias globally are attributable to modifiable risk factors. Many existing studies examining attitudes to brain health are limited by a failure to consider a range of pertinent risk factors and associated barriers to protective behaviors. In Ireland, self-reported knowledge of dementia is poor compared to other conditions. In this context, the current study aimed to explore exposure to and awareness of specific modifiable risk factors for dementia. We also aimed to investigate whether exposure to these risk factors is associated with demographic and socioeconomic factors. A cross-sectional survey was administered to 555 voluntary participants in February 2022. The survey captured the following information: (1) Sociodemographic factors; (2) Exposure to, as well as knowledge of modifiable risk factors for dementia, namely diet, social interaction, exercise, hypertension, sleep, depression, smoking, alcohol consumption, cognitive stimulation, hearing impairment, diabetes, air pollution, and head injury. The study population comprised 551 participants (50.3% male; 49.6% female). Mean age was 59.7 years. Modifiable risk factors for dementia were prevalent. Relative to females, male gender was significantly associated with multiple risk factors. Whilst 65.6% of participants believed that lifestyle improvements can decrease a person's risk of developing dementia, only 31.4% believed that dementia could be prevented. Head injury (90.9%, n = 500), low mental stimulation (85.3%, n = 469), and alcohol consumption (77.8%, n = 428) were the three most commonly recognized risk factors. Awareness was significantly greater in both university groups (undergraduate and postgraduate) for multiple risk factors. Our findings demonstrate that the distribution of exposure to modifiable risk factors for dementia is unequal across gender and age groups, and that awareness levels vary across risk factors. These findings highlight that focus surrounding dementia prevention should shift toward individual risk profiling and should be tailored toward an individual's specific needs., Competing Interests: EGL and KM were previously employed by Five Lives SAS/SharpTx Ltd. LJ, PV, and IK are employed by Five Lives SAS/SharpTx Ltd. This study received funding from Five Lives SAS/SharpTx Ltd., who sponsored performance of the survey. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Dukelow, Lawrence, Jacobson, Vassilev, Koychev, Muhammed and Kennelly.)

Introduction: Economic evaluation currently focuses almost exclusively on the maximization of health, using the Quality-Adjusted Life-Year (QALY) framework with instruments such as the EQ-5D, with a limited number of health-focused dimensions providing the assessment of health benefit. This evaluative framework is likely to be insufficient for setting priorities in dementia care because of its exclusive concern with health. Data are also often collected from the perspective of a proxy, limiting the voice of those living with dementia in decision-making. This protocol describes a research project that aims to gather the perspectives of people living with dementia, their insights, and preferences for assessing their quality of life to inform economic evaluation outcome measurement and design with a goal of creating a more robust evidence base for the value of healthcare services. Specifically, this study will elucidate what a "good life" means to people living with dementia and how well instruments currently used in economic evaluation meet this description. This project will further test the acceptability of capability wellbeing instruments as self-report instruments and compare them to generic and dementia-specific preference-based instruments., Methods and Analysis: People living with dementia, diagnosed, or waiting to receive a formal diagnosis and with the capacity to participate in research, will be invited to participate in an hour "think aloud" interview. Participants will be purposefully selected to cover a range of dementia diagnoses, age, and sex, recruited through the integrated care, geriatric, and post-diagnostic clinics at St James' and Tallaght University Hospitals and dementia support groups in the Ireland. During the interview, participants will be invited to reflect on a "good life" and "think aloud" while completing four economic quality of life instruments with a perspective that goes beyond health (AD-5D/QOL-AD, AQOL-4D, ICECAP-O, ICECAP-SCM). An interviewer will then probe areas of difficulty when completing the instruments in a semi-structured way. The analysis will identify the frequency of errors in comprehension, retrieval, judgment, and response from verbatim transcripts. Qualitative data will be analyzed using constant comparison., Ethics: The St James's Hospital and Tallaght University Hospital Joint Research Ethics Committee approved the study (Approval Date: 11 April 2022)., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Kinchin, Leroi, Kennelly, Kochovska, Brady, Fitzhenry, McHale, Kinghorn and Coast.)

Midlife Type 2 Diabetes Mellitus (T2DM) is associated with an increased risk of Alzheimer Disease (AD) in later life, with altered inflammatory responses postulated as key pathological drivers. Previous studies have demonstrated increased responsiveness to NLR family pyrin domain containing 3 (NLRP3) inflammasome agonists, both in individuals with untreated T2DM in addition to those with established AD. We hypothesised that peripheral NLRP3 inflammasome responses may be altered during the early stages of T2DM-related cognitive dysfunction. Here, we assessed the relationship between NLPR3 responses in peripheral blood mononuclear cells (including to Aβ-42, the putative pathogenic protein in AD) and neuropsychological performance in uncomplicated midlife T2DM to identify early signatures of immune dysregulation which may predispose to later cognitive decline. We recruited a cross-sectional cohort of middle-aged adults with uncomplicated T2DM and matched Healthy Controls (HCs) for comprehensive neuropsychological assessment and in vitro PBMC responses to a range of NLRP3 agonists were assessed. T2DM was associated with subtle decrements on neuropsychological tests of delayed memory and executive function (both p<0.05). Overall, there were no differences between T2DM and HCs in immune responses induced by NLRP3 agonists. Further, we observed no relationship between the subtle neuropsychological decrements observed in T2DM and PBMC responsiveness to NLRP3 agonists. Our data suggests that peripheral NLRP3 inflammasome response dysregulation may not play a role in the early stages of cognitive dysfunction in midlife T2DM. Further longitudinal studies are warranted to examine the contribution of peripheral NLRP3 responses towards disease pathology and as cognitive decline accelerates in T2DM., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Dyer, Batten, Reddy, Townsend, Woods, O’Neill, Gibney, Kennelly and Bourke.)

The misattribution of an adverse drug reaction (ADR) as a symptom or illness can lead to the prescribing of additional medication, referred to as a prescribing cascade. The aim of this systematic review is to identify published prescribing cascades in community-dwelling adults. A systematic review was reported in line with the PRISMA guidelines and pre-registered with PROSPERO. Electronic databases (Medline [Ovid], EMBASE, PsycINFO, CINAHL, Cochrane Library) and grey literature sources were searched. Inclusion criteria: community-dwelling adults; risk-prescription medication; outcomes-initiation of new medicine to "treat" or reduce ADR risk; study type-cohort, cross-sectional, case-control, and case-series studies. Title/abstract screening, full-text screening, data extraction, and methodological quality assessment were conducted independently in duplicate. A narrative synthesis was conducted. A total of 101 studies (reported in 103 publications) were included. Study sample sizes ranged from 126 to 11 593 989 participants and 15 studies examined older adults specifically (≥60 years). Seventy-eight of 101 studies reported a potential prescribing cascade including calcium channel blockers to loop diuretic (n = 5), amiodarone to levothyroxine (n = 5), inhaled corticosteroid to topical antifungal (n = 4), antipsychotic to anti-Parkinson drug (n = 4), and acetylcholinesterase inhibitor to urinary incontinence drugs (n = 4). Identified prescribing cascades occurred within three months to one year following initial medication. Methodological quality varied across included studies. Prescribing cascades occur for a broad range of medications. ADRs should be included in the differential diagnosis for patients presenting with new symptoms, particularly older adults and those who started a new medication in the preceding 12 months., (© 2022 The Authors. Pharmacology Research & Perspectives published by British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics and John Wiley & Sons Ltd.)

Older adults in nursing homes are at greatest risk of morbidity and mortality from SARS-CoV-2 infection. Nursing home residents constituted one-third to more than half of all deaths during the early waves of the COVID-19 pandemic. Following this, widespread adaptation of infection prevention and control measures and the supply and use of personal protective equipment resulted in a significant decrease in nursing home infections and deaths. For nursing homes, the most important determinant of experiencing a SARS-CoV-2 outbreak in the first instance appears to be community-transmission levels (particularly with variants of concern), although nursing home size and quality, for-profit status, and sociodemographic characteristics are also important. Use of visitation bans, imposed to reduce the impact of COVID-19 on residents, must be delicately balanced against their impact on resident, friend or family, and staff well-being. The successful rollout of primary vaccination has resulted in a sharp decrease in morbidity and mortality from SARS-CoV-2 in nursing homes. However, emerging evidence suggests that vaccine efficacy may wane over time, and the use of a third or additional vaccine "booster" doses in nursing home residents restores protection afforded by primary vaccination. Ongoing monitoring of vaccine efficacy in terms of infection, morbidity, and mortality is crucial in this vulnerable group in informing ongoing SARS-CoV-2 vaccine boosting strategies. Here, we detail the impact of SARS-CoV-2 on nursing home residents and discuss important considerations in the management of nursing home SARS-CoV-2 outbreaks. We additionally examine the use of testing strategies, nonpharmacologic outbreak control measures and vaccination strategies in this cohort. Finally, the impact of SARS-CoV-2 on the sector is reflected on as we emphasize the need for adoption of universal standards of medical care and integration with wider public health infrastructure in nursing homes in order to provide a safe and effective long-term care sector., (Copyright © 2022 AMDA – The Society for Post-Acute and Long-Term Care Medicine. Published by Elsevier Inc. All rights reserved.)

Objectives: Aducanumab is a monoclonal antibody which has recently been licenced for use by the food and drug administration for treatment of patients with mild cognitive impairment due to Alzheimer's disease (AD) or mild AD dementia. Appropriate use criteria (AUC) for Aducanumab in clinical practice are available. We look to review patients in our specialist interdisciplinary cognitive service with positive cerebrospinal fluid (CSF) biomarkers for AD for their hypothetical eligibility for Aducanumab, or a similar anti-amyloid agent., Methods: Retrospective analysis was undertaken of patients with positive AD-biomarker CSF analysis. Data available at time of CSF analysis was reviewed to determine hypothetical eligibility for Aducanumab., Results: Seventy patients had positive AD-CSF biomarkers. Forty nine of these were seen in the Gerontology-led service, with 21 in the neurology cohort. Average patient age was 70 years old. Forty patients (57%) met eligibility criteria for Aducanumab therapy by AUC guidelines., Conclusion: We highlight the patients within our service who would be appropriate for Aducanumab or similar anti-amyloid agents should licencing be granted in the European Union, and the need to develop the resources and capacity to deliver this or other emerging disease modifying AD therapies., Clinical Trial Registration: All patients in the combined cognitive clinic provide consent re willingness to be contacted re research., (© 2022 The Authors. International Journal of Geriatric Psychiatry published by John Wiley & Sons Ltd.)

Type 2 Diabetes Mellitus (T2DM) in midlife is associated with a greater risk of dementia in later life. Both gait speed and spatiotemporal gait characteristics have been associated with later cognitive decline in community-dwelling older adults. Thus, the assessment of gait characteristics in uncomplicated midlife T2DM may be important in selecting-out those with T2DM at greatest risk of later cognitive decline. We assessed the relationship between Inertial Motion Unit (IMUs)-derived gait characteristics and cognitive function assessed via Montreal Cognitive Assessment (MoCA)/detailed neuropsychological assessment battery (CANTAB) in middle-aged adults with and without uncomplicated T2DM using both multivariate linear regression and a neural network approach. Gait was assessed under (i) normal walking, (ii) fast (maximal) walking and (iii) cognitive dual-task walking (reciting alternate letters of the alphabet) conditions. Overall, 138 individuals were recruited (n = 94 with T2DM; 53% female, 52.8 ± 8.3 years; n = 44 healthy controls, 43% female, 51.9 ± 8.1 years). Midlife T2DM was associated with significantly slower gait velocity on both slow and fast walks (both p < 0.01) in addition to a longer stride time and greater gait complexity during normal walk (both p < 0.05). Findings persisted following covariate adjustment. In analyzing cognitive performance, the strongest association was observed between gait velocity and global cognitive function (MoCA). Significant associations were also observed between immediate/delayed memory performance and gait velocity. Analysis using a neural network approach did not outperform multivariate linear regression in predicting cognitive function (MoCA) from gait velocity. Our study demonstrates the impact of uncomplicated T2DM on gait speed and gait characteristics in midlife, in addition to the striking relationship between gait characteristics and global cognitive function/memory performance in midlife. Further studies are needed to evaluate the longitudinal relationship between midlife gait characteristics and later cognitive decline, which may aid in selecting-out those with T2DM at greatest-risk for preventative interventions.

Serological assays capable of measuring antibody responses induced by previous infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been critical tools in the response to the COVID-19 pandemic. In this study, we use bead-based multiplex assays to measure IgG and IgA antibodies and IgG avidity to five SARS-CoV-2 antigens (Spike (S), receptor-binding domain (RBD), Nucleocapsid (N), S subunit 2, and Membrane-Envelope fusion (ME)). These assays were performed in several cohorts of healthcare workers and nursing home residents, who were followed for up to eleven months after SARS-CoV-2 infection or up to six months after vaccination. Our results show distinct kinetic patterns of antibody quantity (IgG and IgA) and avidity. While IgG and IgA antibody levels waned over time, with IgA antibody levels waning more rapidly, avidity increased with time after infection or vaccination. These contrasting kinetic patterns allow for the estimation of time since previous SARS-CoV-2 infection. Including avidity measurements in addition to antibody levels in a classification algorithm for estimating time since infection led to a substantial improvement in accuracy, from 62% to 78%. The inclusion of antibody avidity in panels of serological assays can yield valuable information for improving serosurveillance during SARS-CoV-2 epidemics.

The vagus nerve is the longest nerve in the human body, providing afferent information about visceral sensation, integrity and somatic sensations to the CNS via brainstem nuclei to subcortical and cortical structures. Its efferent arm influences GI motility and secretion, cardiac ionotropy, chonotropy and heart rate variability, blood pressure responses, bronchoconstriction and modulates gag and cough responses via palatine and pharyngeal innervation. Vagus nerve stimulation has been utilized as a successful treatment for intractable epilepsy and treatment-resistant depression, and new non-invasive transcutaneous (t-VNS) devices offer equivalent therapeutic potential as invasive devices without the surgical risks. t-VNS offers exciting potential as a therapeutic intervention in cognitive decline and aging populations, classically affected by reduced cerebral perfusion by modulating both limbic and frontal cortical structures, regulating cerebral perfusion and improving parasympathetic modulation of the cardiovascular system. In this narrative review we summarize the research to date investigating the cognitive effects of VNS therapy, and its effects on neurocardiovascular stability., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Dolphin, Dukelow, Finucane, Commins, McElwaine and Kennelly.)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection fatality rate (IFR) doubles with every 5 y of age from childhood onward. Circulating autoantibodies neutralizing IFN-α, IFN-ω, and/or IFN-β are found in ∼20% of deceased patients across age groups, and in ∼1% of individuals aged <70 y and in >4% of those >70 y old in the general population. With a sample of 1,261 unvaccinated deceased patients and 34,159 individuals of the general population sampled before the pandemic, we estimated both IFR and relative risk of death (RRD) across age groups for individuals carrying autoantibodies neutralizing type I IFNs, relative to noncarriers. The RRD associated with any combination of autoantibodies was higher in subjects under 70 y old. For autoantibodies neutralizing IFN-α2 or IFN-ω, the RRDs were 17.0 (95% CI: 11.7 to 24.7) and 5.8 (4.5 to 7.4) for individuals <70 y and ≥70 y old, respectively, whereas, for autoantibodies neutralizing both molecules, the RRDs were 188.3 (44.8 to 774.4) and 7.2 (5.0 to 10.3), respectively. In contrast, IFRs increased with age, ranging from 0.17% (0.12 to 0.31) for individuals <40 y old to 26.7% (20.3 to 35.2) for those ≥80 y old for autoantibodies neutralizing IFN-α2 or IFN-ω, and from 0.84% (0.31 to 8.28) to 40.5% (27.82 to 61.20) for autoantibodies neutralizing both. Autoantibodies against type I IFNs increase IFRs, and are associated with high RRDs, especially when neutralizing both IFN-α2 and IFN-ω. Remarkably, IFRs increase with age, whereas RRDs decrease with age. Autoimmunity to type I IFNs is a strong and common predictor of COVID-19 death.

Objectives: Older nursing home residents make up the population at greatest risk of morbidity and mortality from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. No studies have examined the determinants of long-term antibody responses post vaccination in this group., Design: Longitudinal cohort study., Setting and Participants: Residents from 5 nursing homes assessed before vaccination, and 5 weeks and 6 months post vaccination, with the BNT162b2 messenger RNA SARS-CoV-2 vaccine., Methods: Comprehensive clinical assessment was performed, including assessment for comorbidity, frailty, and SARS-CoV-2 infection history. Serum nucleocapsid and anti-spike receptor binding domain (RBD) antibodies were analyzed at all timepoints. An in vitro angiotensin-converting enzyme (ACE2) receptor-spike RBD neutralization assay assessed serum neutralization capacity., Results: Of 86 participants (81.1 ± 10.8 years; 65% female), just under half (45.4%; 39 of 86) had evidence of previous SARS-CoV-2 infection. All participants demonstrated a significant antibody response to vaccination at 5 weeks and a significant decline in this response by 6 months. SARS-CoV-2 infection history was the strongest predictor of antibody titer (log-transformed) at both 5 weeks [β: 3.00; 95% confidence interval (CI): 2.32-3.70; P < .001] and 6 months (β: 3.59; 95% CI: 2.89-4.28; P < .001). Independent of SARS-CoV-2 infection history, both age in years (β: -0.05; 95% CI: -0.08 to -0.02; P < .001) and frailty (β: -0.22; 95% CI: -0.33 to -0.11; P < .001) were associated with a significantly lower antibody titer at 6 months. Anti-spike antibody titers at both 5 weeks and 6 months significantly correlated with in vitro neutralization capacity., Conclusions and Implications: In older nursing home residents, SARS-CoV-2 infection history was the strongest predictor of anti-spike antibody titers at 6 months, whereas age and frailty were independently associated with lower titers at 6 months. Antibody titers significantly correlated with in vitro neutralization capacity. Although older SARS-CoV-2 naïve nursing home residents may be particularly vulnerable to breakthrough SARS-CoV-2 infection, the relationship between antibody titers, SARS-CoV-2 infection, and clinical outcomes remains to be fully elucidated in this vulnerable population., (Copyright © 2021 AMDA – The Society for Post-Acute and Long-Term Care Medicine. Published by Elsevier Inc. All rights reserved.)

Background: With the evolving knowledge on hearing as a potentially modifiable mid-life risk factor for dementia, identification of people at risk becomes increasingly important. People with mild cognitive impairment (MCI) presenting to specialist memory services represent a key "at-risk" target population for audiological evaluation, but few services have established this pathway. This study sought to examine the patient experience and understanding of this process., Methods: All patients with MCI attending a tertiary referral memory service referred for audiology review were contacted. A patient survey was delivered over the phone. Outpatient letters and the memory clinic database were reviewed., Results: Twenty patients with MCI were included in the survey. Eight (8/20, 40%) had self-reported hearing loss. Upon formal audiological assessment seventeen (17/20, 85%) had objective evidence of hearing loss; nine (9/17, 52.9%) with mild-moderate and eight (8/17, 47%) with moderate-severe hearing loss. Only six patients (6/20, 30%) recalled having the rationale behind having a hearing test as part of their memory work-up explained to them. However, the majority (15/20, 75%) felt a hearing test was an important part of their memory assessment. Just seven patients overall (7/20, 35%) identified a link between hearing-loss and cognition. All patients who provided feedback on the service itself made positive comments, although (4/20, 20%) felt they did not get adequate information about the results., Conclusions: A significant proportion of people with MCI had de-novo evidence of hearing impairment upon assessment. Patients are satisfied with incorporating audiological evaluation into a memory clinic assessment, however clear communication around indication, recommendations, and follow-up ensuring compliance is required., (© 2021. The Author(s).)

Background: Medication reconciliation (MedRec), a process to reduce medication error at care transitions, is labour- and resource-intensive and time-consuming. Use of Personal Electronic Records of Medications (PERMs) in health information systems to support MedRec have proven challenging. Relatively little is known about the design, use or implementation of PERMs at care transitions that impacts on MedRec in the 'real world'. To respond to this gap in knowledge we undertook a rapid realist review (RRR). The aim was to develop theories to explain how, why, when, where and for whom PERMs are designed, implemented or used in practice at care transitions that impacts on MedRec., Methodology: We used realist methodology and undertook the RRR between August 2020 and February 2021. We collaborated with experts in the field to identify key themes. Articles were sourced from four databases (Pubmed, Embase, CINAHL Complete and OpenGrey) to contribute to the theory development. Quality assessment, screening and data extraction using NVivo was completed. Contexts, mechanisms and outcomes configurations were identified and synthesised. The experts considered these theories for relevance and practicality and suggested refinements., Results: Ten provisional theories were identified from 19 articles. Some theories relate to the design (T2 Inclusive design, T3 PERMs complement existing good processes, T7 Interoperability), some relate to the implementation (T5 Tailored training, T9 Positive impact of legislation or governance), some relate to use (T6 Support and on-demand training) and others relate iteratively to all stages of the process (T1 Engage stakeholders, T4 Build trust, T8 Resource investment, T10 Patients as users of PERMs)., Conclusions: This RRR has allowed additional valuable data to be extracted from existing primary research, with minimal resources, that may impact positively on future developments in this area. The theories are interdependent to a greater or lesser extent; several or all of the theories may need to be in play to collectively impact on the design, implementation or use of PERMs for MedRec at care transitions. These theories should now be incorporated into an intervention and evaluated to further test their validity., (© 2021. The Author(s).)

Introduction: Previous evidence has suggested that antipsychotic use may be associated with accelerated cognitive decline in those living with dementia. However, the cognitive effects of long-term antipsychotic use in community-dwelling older adults with mild-moderate Alzheimer disease (AD) has not been explored to date., Methods: We assessed the impact of long-term antipsychotic use on the rate of cognitive decline (Alzheimer's Disease Assessment Scale-Cognitive Subsection) and dementia progression (Clinical Dementia Rating-Sum of Boxes [CDR-Sb]/Disability Assessment for Dementia [DAD]) over 18 months in older adults with mild-moderate AD., Results: Of 509 participants with mild-moderate AD, one-tenth (54/509; 10.6%) were prescribed an antipsychotic for the 18-month study duration. Antipsychotic use was significantly associated with accelerated cognitive decline at both 12 (β: 3.53, 0.91-6.17, p = 0.008) and 18 months (β: 3.81, 0.49-7.14, p = 0.024) in addition to greater dementia progression at both 12 (β: 1.85, -0.97-2.73, p < 0.001 for CDR-Sb/β: -3.33, -5.56-1.10, p = 0.003 for DAD) and 18 months (β: 1.41, 0.16-2.67, p = 0.027 for CDR-Sb/β: -3.86, -6.64 to -1.08, p = 0.006 for DAD). APOE ε4 carriers experienced significantly greater cognitive decline with long-term antipsychotic use., Conclusions: Long-term antipsychotic use was associated with greater cognitive decline and dementia progression in community-dwelling older adults with mild-moderate AD. Our findings are consistent with previous evidence encouraging cautious and careful consideration of risks versus benefits of antipsychotic usage in those with AD., (© 2021 The Authors. International Journal of Geriatric Psychiatry published by John Wiley & Sons Ltd.)

Objectives: Poor social networks are associated with a greater likelihood of cognitive decline, dementia, and other adverse health outcomes in later life. However, these relationships have been poorly explored in those with established Alzheimer Disease (AD), who may represent a particularly vulnerable group., Methods: Analysis of data from the NILVAD study. We assessed social networks (Lubben Social Network Scale [LSNS]), cognition (Alzheimer's disease Assessment Scale [ADAS-Cog]) and dementia severity (Clinical Dementia Rating, Sum of Boxes [CDR-Sb]) in older adults with mild-moderate AD at baseline and at 18 months., Results: 464 participants with mild-to-moderate AD were included (73.1 ± 8.3 years; 61.9% female). At baseline, a poor social network was significantly associated with a greater dementia severity, but not greater cognitive impairment. Rather than a poor social network predicting greater cognitive decline over 18 months, a greater baseline dementia severity predicted a decline in social network over 18 months (β: -0.22, -0.42 - -0.02, p  = 0.034). Finally, a poor social network was associated with a significantly increased likelihood of experiencing serious adverse events (IRR: 1.41, 1.06-1.89, p  = 0.019)., Discussion: As dementia progresses, older adults with AD are more likely to experience a decline in social network. Further, having a poor social network was associated with a greater likelihood of experiencing serious adverse events. These findings add novel insight into the complex relationship between social networks, dementia progression and adverse events in AD, and underscore the importance of developing and maintaining social networks in AD.

Circulating autoantibodies (auto-Abs) neutralizing high concentrations (10 ng/mL, in plasma diluted 1 to 10) of IFN-α and/or -ω are found in about 10% of patients with critical COVID-19 pneumonia, but not in subjects with asymptomatic infections. We detect auto-Abs neutralizing 100-fold lower, more physiological, concentrations of IFN-α and/or -ω (100 pg/mL, in 1/10 dilutions of plasma) in 13.6% of 3,595 patients with critical COVID-19, including 21% of 374 patients > 80 years, and 6.5% of 522 patients with severe COVID-19. These antibodies are also detected in 18% of the 1,124 deceased patients (aged 20 days-99 years; mean: 70 years). Moreover, another 1.3% of patients with critical COVID-19 and 0.9% of the deceased patients have auto-Abs neutralizing high concentrations of IFN-β. We also show, in a sample of 34,159 uninfected subjects from the general population, that auto-Abs neutralizing high concentrations of IFN-α and/or -ω are present in 0.18% of individuals between 18 and 69 years, 1.1% between 70 and 79 years, and 3.4% >80 years. Moreover, the proportion of subjects carrying auto-Abs neutralizing lower concentrations is greater in a subsample of 10,778 uninfected individuals: 1% of individuals <70 years, 2.3% between 70 and 80 years, and 6.3% >80 years. By contrast, auto-Abs neutralizing IFN-β do not become more frequent with age. Auto-Abs neutralizing type I IFNs predate SARS-CoV-2 infection and sharply increase in prevalence after the age of 70 years. They account for about 20% of both critical COVID-19 cases in the over-80s, and total fatal COVID-19 cases., (Copyright © 2021, American Association for the Advancement of Science.)

Aims: To establish the impact of uncomplicated type 2 diabetes on cognitive and neuropsychological performance in midlife., Methods: We performed a cross-sectional study of middle-aged adults with uncomplicated type 2 diabetes and a cohort of healthy control participants. General cognition was assessed using the Montreal Cognitive Assessment test and neuropsychological assessment was undertaken using a detailed neuropsychological assessment battery., Results: A total of 152 participants (102 with type 2 diabetes and 50 controls) were recruited (mean age 52 ± 8 years, 51% women). Participants with midlife type 2 diabetes were more than twice as likely to make an error on the Montreal Cognitive Assessment test [incidence rate ratio 2.44 (95% CI 1.54 to 3.87); P < 0.001]. Further, type 2 diabetes was also associated with significantly lower memory composite score [β: -0.20 (95% CI -0.39 to -0.01); P = 0.04] and paired associates learning score [β: = -1.97 (95% CI -3.51, -0.43); P = 0.01] on the neuropsychological assessment battery following adjustment for age, sex, BMI, educational attainment and hypercholesterolaemia., Conclusions: Even in midlife, type 2 diabetes was associated with small but statistically significant cognitive decrements. These statistically significant decrements, whilst not clinically significant in terms of objective cognitive impairment, may have important implications in selecting out individuals most at risk of later cognitive decline for potential preventative interventions in midlife., (© 2020 Diabetes UK.)

Purpose: Cognitive impairment is a well-reported side-effect of chemotherapy in persons with breast cancer. Whilst non-pharmacological interventions have proven efficacious in the management of cognitive impairment in high-risk groups, their efficacy in cognitive impairment post-chemotherapy in patients with breast cancer remains unclear., Methods: Medline, CINAHL, PsycINFO, Web of Science and Cochrane were searched for randomized controlled trials of non-pharmacological interventions for cognitive impairment post-chemotherapy in women with breast cancer., Results: Of 429 results, 83 full-texts were reviewed with ten meeting inclusion criteria. Interventions included cognitive training, exercise and complementary therapies. The non-pharmacological interventions assessed displayed variable benefits in subjective and/or objective cognitive assessments, with no strong evidence for beneficial effects across included studies. No studies assessed the efficacy of multi-domain interventions., Conclusions: There is mixed evidence supporting non-pharmacological interventions for cognitive impairment post-chemotherapy in women with breast cancer. Moving forward, multidomain trials combining non-pharmacological interventions are imperative in this high risk cohort., (Copyright © 2020 Elsevier Inc. All rights reserved.)