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Changes in the levels of circulating proteins are associated with Alzheimer's disease (AD), whereas their pathogenic roles in AD are unclear. Here, we identified soluble ST2 (sST2), a decoy receptor of interleukin-33-ST2 signaling, as a new disease-causing factor in AD. Increased circulating sST2 level is associated with more severe pathological changes in female individuals with AD. Genome-wide association analysis and CRISPR-Cas9 genome editing identified rs1921622 , a genetic variant in an enhancer element of IL1RL1, which downregulates gene and protein levels of sST2. Mendelian randomization analysis using genetic variants, including rs1921622 , demonstrated that decreased sST2 levels lower AD risk and related endophenotypes in females carrying the Apolipoprotein E (APOE)-ε4 genotype; the association is stronger in Chinese than in European-descent populations. Human and mouse transcriptome and immunohistochemical studies showed that rs1921622 /sST2 regulates amyloid-beta (Aβ) pathology through the modulation of microglial activation and Aβ clearance. These findings demonstrate how sST2 level is modulated by a genetic variation and plays a disease-causing role in females with AD.

Introduction: The pursuit of Equity, Diversity and Inclusion (EDI) in healthcare education has garnered significant attention in recent years, reflecting a broader societal imperative for equitable healthcare delivery. However, existing curricula within geriatric healthcare education may not adequately address these diverse needs within their educational frameworks, inadvertently resulting in disparities in care delivery and outcomes. Within the realm of geriatric healthcare, addressing EDI is particularly crucial due to the diverse needs of older adult populations and the imperative for healthcare professionals to deliver culturally humble care. This review provides a comprehensive overview of strategies and curricular strategies, actions and/or initiatives to promote EDI within geriatric healthcare professional education. Methods: This paper presents a protocol for a forthcoming scoping review. The methodology for this scoping review adheres to the framework outlined in the Joanna Briggs Institute (JBI) Manual, encompassing four main stages: (1) formulation of a search strategy, (2) screening and selection of evidence, (3) data extraction, and (4) analysis. We will conduct a comprehensive search of peer-reviewed and empirical literature. Additionally, we will explore the reference lists of included studies to identify any relevant sources. The synthesis of findings will be conducted through a narrative approach. Reporting of the methods and results will adhere to the guidelines provided by the Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR). Discussion: Healthcare professionals must possess the knowledge, skills, and attitudes necessary to deliver culturally humble care that respects and responds to diverse older adults' unique needs and preferences. The review aims to fill a crucial gap in the literature by providing a comprehensive overview of strategies and curricular interventions designed to promote EDI within geriatric healthcare professional education. By mapping these strategies, actions and/or initiatives, the review seeks to identify trends, challenges, and opportunities for advancing EDI within geriatric care. The forthcoming review serves as a call to action for educators, healthcare institutions, and decision makers to prioritize EDI within geriatric healthcare education. The review identifies effective strategies and interventions for promoting EDI, providing actionable insights to inform the development of inclusive curricula, training programs, and institutional policies, which can contribute to cultivating a healthcare workforce better equipped to address the complex and evolving needs of aging populations equitably and compassionately. [ABSTRACT FROM AUTHOR]

Objective: We assessed the accuracy of the ICD-10 code for delirium (F05) and its relationship with delirium discharge summary documentation. Methods: We performed a retrospective chart review at three academic hospitals. The Chart-based Delirium Identification Instrument (CHART-DEL) was used to identify 108 hospitalized patients aged ≥65 years with delirium, and 758 patients without delirium as controls. We assessed the proportion of patients who received the F05 code and calculated the sensitivity and specificity. We compared the rates of F05 code received between patients with and without "delirium" documented in the discharge summary. Results: Among delirious patients, 46.3% received a F05 code, which has a sensitivity of 46.3% and specificity of 99.6% for delirium. Of charts with "delirium" in the discharge summary (n = 67), 67.2% were appropriately coded. Conclusions: Current ICD-10 data inadequately capture delirium. Delirium documentation in the discharge summary is associated with improved delirium coding. [ABSTRACT FROM AUTHOR]

Older adults with functional impairment are cared for by physiatrists in rehabilitation, but physiatrist training in geriatric-related competencies remains suboptimal. To develop a geriatric rehabilitation (GR) curriculum and explore opportunities for improvement, a needs assessment of stakeholders was conducted to understand physical medicine and rehabilitation (PMR) residents' comfort levels and learning needs in geriatrics. A mixed-methods design was employed. PMR residents (n = 18) and practicing physiatrists (n = 40) completed a questionnaire; and PMR residents, physiatrists and key informants (n = 9; n = 4; n = 6) participated in focus groups and semi-structured interviews to explore geriatric experiences of trainees and educational needs in geriatrics and rehabilitation. Data were qualitatively analyzed using constructivist-grounded theory. Residents and physiatrists highlighted similar topics as areas of low comfort in knowledge. Interviews prioritized critical geriatric topics (gait assessment, falls, cognitive impairment, movement disorders, and polypharmacy) and highlighted disposition planning and end-of-life care as areas needing further curriculum support. Challenges in delivering geriatric education were also identified. What emerged from the needs assessment was a series of critical geriatric educational priorities for the development of a GR curriculum for physiatry trainees – arising at an opportune time given the shift toward competency-based residency education. [ABSTRACT FROM AUTHOR]

Background: Brain perfusion and blood brain barrier (BBB) integrity are reduced in Alzheimer's disease (AD). We hypothesized that b‐amyloid (Aβ) induces dysfunction of pathways in vascular cells that regulate angiogenesis. Method: We performed single nucleus RNA sequencing (snRNAseq) of vascular cells isolated from post mortem samples from multiple cortical regions from AD patients (Braak V‐VI) and non‐diseased controls (NDC, Braak 0‐II). We developed a meta‐analytic approach to integrate these data with related publicly available datasets. We performed differential gene expression (DGE) analyses as a categorical comparison of AD vs NDC and as a confound‐controlled regression of transcriptomic alterations by regional total Aβ. We also performed cell‐specific gene co‐expression analyses identify modules differentially expressed in AD relative to NDC. Result: Our results describe differential expression of genes central to pathways sustaining angiogenesis, proliferation and migration of endothelial cells and the integrity of the BBB with either AD or greater pathological protein load. HIF1A and FGF2, proangiogenic molecules which both induce VEGF, are upregulated in EC, consistent the parenchymal hypoxic response shown repeatedly in prior studies. However, components of signalling pathways downstream of VEGFR2 are downregulated, suggesting a pathological block to angiogenesis with greater Aβ load. While the proangiogenic stimuli promote the expression of genes such as PPP3CA and ITPR1, coding for calcineurin, which contribute to VEGF signalling through the PLCγ‐Ca2+ signalling pathway are upregulated in AD, expression of RAC1 and RHOJ, which enable cellular migration and adhesion, is downregulated. While ANGPT2 expression is also upregulated, the angiopoietin receptor (TIE2, coded by TEK) is downregulated. Downregulation of ADAM10 in AD and upregulation of other NOTCH pathway genes with greater Aβ load suggests altered NOTCH signalling. Conclusion: Overall, a hypoxic tissue environment in AD is accompanied by dysfunctional angiogenesis related to Aβ load. Evidence for multiple sites of dysfunction were identified, involving impaired angiopoietin responses, vascular cell migration and NOTCH signaling. [ABSTRACT FROM AUTHOR]

Background: Coding variants in the microglial TREM2 ectodomain differentially (R47H> R62H) increase the risk of Alzheimer's disease (AD). To define mechanisms responsible in glia and neurons, we aimed to characterise neuropathology and transcriptomic responses in heterozygotes for these TREM2 variant alleles and for common allele homozygotes (CV) in non‐diseased (n = 16) and AD (n = 42) brain cortical tissue from 58 donors. Method: Using immunohistochemistry (IHC) and imaging mass cytometry (IMC), we characterised neocortical b‐amyloid and AT8/PHF1 pTau pathology with CV (n = 30) and the R47H (n = 11) or R62H (n = 17) TREM2 carriers. We performed single nuclear RNA sequencing to test for the differential gene expression (DGE) in TREM2 and CV cortical tissues with greater 4G8+ b‐amyloid‐ or PHF1+ pTau‐immunostaining. Result: There was a two‐fold increase in 4G8+, a three‐fold reduction in AT8+ but no change in PHF1+ immunostaining with AD in both variants versus CV. We found a reduced expression of genes associated with TREM2 function in R47H carriers relative to CV however enhanced microglial activation in R62H carriers. This was associated with an up‐regulation of pathways such as 'neuroinflammation signalling pathway' in R62H not seen in R47H. CV astrocytes had little DGE with increasing pathology however both variants (R47H>R62H) had an increased proportion of differentially expressed genes suggestive of a heightened activation state. R47H and R62H astrocytes impacted pathways had opposing actions such as 'synaptogenesis signalling pathway' and 'PDGF signalling' pathways downregulated in R47H but upregulated in R62H. Neuronal gene expression changes were evident in all variants, however greatly enhanced in R47H in response to 4G8+ b‐amyloid. With increasing PHF1+ pTau gene expression changes were mainly seen in R47H. Excitatory and inhibitory neurons both exhibited DGE in R47H carriers and impacted pathways centred around those involved in 'synaptogenesis signalling pathway', 'SNARE signalling pathway' and 'synaptic long term depression'. Conclusion: This analysis identified novel disease‐associated transcriptomic differences in the glial response to TREM2 and the secondary neuronal responses that can explain differences in the genetic AD risk conferred by these two TREM2 risk variants. [ABSTRACT FROM AUTHOR]

Background: Ageing is the greatest risk factor for Alzheimer's disease (AD). While accumulation of senescent cells is one of the major hallmarks of ageing, the effect of the senescence burden is yet to be explored in AD. The aims of this study were to i) quantify senescent microglia, oligodendrocyte and astrocyte in human brain in AD, ii) determine the driver of cell senescence in AD, and iii) AD pathology associated senescence. Method: We multiplexed Image Mass Cytometry (IMC) to co‐localise cell type markers (IBA1, OLIG2, GFAP), senescence markers (GLB1 and p16) and β‐amyloid (4G8) to detect senescence in tissues from Middle Temporal Gyrus (MTG) of 10 AD and 10 non‐disease control (NDC). We also generated snRNA‐seq from three different brain regions of the same subject namely Entorhinal (EC), MTG (Mid‐temporal Cortex) and Somatosensory Cortex (SSC) of 9 AD and 9 NDC. We performed geneset enrichment analysis using a set of curated senescence associated genesets in snRNA‐seq using AUcell and dream (variancePartition). We further performed trajectory analysis using Monocle3 to characterise β‐amyloid associated senescence signatures in the snRNAseq data. Result: More than 25% microglia, oligodendrocyte and astrocyte were positive for GLB1 in AD brains while only around 5% glia showed GLB1 expression in NDC. Around 25% peri‐plaque microglia within 10 µm around β‐amyloid plaques in AD showed expression of GLB1 while only 3% of microglia >10 µm had associated senescence markers. Senescence genes were significantly upregulated in AD compared to NDC and were positively correlated with increase amyloid densities in all three glial cells (not in neurons). Trajectories of the glial nuclei described increased expression of pathways related to replicative senescence, cellular activation and stress response in microglia and oxidative stress in oligodendroglia, and astrocyte. Senescence gene signatures were positively associated with both β‐amyloid and pTau. Conclusion: Our results highlight the high burden of senescent glia and provide evidence for distinct mechanisms of senescence in microglia (both replicative and stress‐induced) relative to oligodendroglia and astrocyte (stress‐induced) in AD. Both β‐amyloid and pTau associated increase in senescence gene signatures suggest that senescence is an important feature in the late stage of AD. [ABSTRACT FROM AUTHOR]

Background: Genetic factors are increasingly being recognized as important contributors to the pathogenesis of Alzheimer's disease (AD). While the expression of most AD risk genes is enriched in microglia, which leads to microglial dysfunction and amyloid‐beta (Aβ) accumulation, emerging studies suggest that changes in the brain micro‐environment—typically changes in the levels of soluble factors—also modulate microglial functions and disease‐related pathological changes. Therefore, understanding the genetic regulation and pathogenic roles of those soluble factors in AD will help clarify the pathophysiological mechanisms of the disease. Method: We examined the changes in the level of soluble ST2 (sST2), a decoy receptor of IL‐33/ST2 signaling, in the blood and brains of patients with AD, and performed a genome‐wide association study (GWAS) for sST2 to understand its genetic regulations. Result: We showed that elevated sST2 levels are associated with more severe neurodegeneration and Aβ pathological lesions in patients with AD. Our GWAS analysis identified a genetic variant in IL1RL1 (the gene encoding sST2) that is associated with decreased sST2 levels in the blood and brain in AD. Furthermore, we demonstrated that female APOE‐ε4 carriers harboring the genetic variant exhibit decreased sST2 level and reduced risk of AD as well as decreased Aβ accumulation through enhancing microglial activation and colocalization with Aβ. Conclusion: These findings demonstrate how sST2 level in the brain milieu is modulated by a genetic variation and plays a disease‐causing role in AD through microglial clearance of Aβ, and might thus be a novel target for AD therapy. [ABSTRACT FROM AUTHOR]

OBJECTIVES: The implementation of competency‐based evaluations increases the emphasis on in‐training assessment. The Consultation Letter Rating Scale (CLRS), published by the Royal College of Physicians and Surgeons of Canada, is a tool that assesses written‐communication competencies. This multisite project evaluated the tool's validity, reliability, feasibility, and acceptability for use in postgraduate geriatric medicine training. METHODS: Geriatric medicine trainees provided consultation letters from the 2017‐2018 academic year. Geriatricians reviewed a standardized module and completed the tool for all the deidentified letters. The reviewers recorded the time used to complete the tool for each letter and completed a survey on content validity. Trainees completed a survey on the tool's usefulness. Responses were reviewed independently by two authors for thematic content. The unweighted and the weighted κ were used to measure interrater reliability. RESULTS: A total of 10 of 11 (91%) eligible trainees each provided five letters that were reviewed independently by six geriatricians, leading to a total of 300 assessments. A very small portion (4% [N = 12]) of assessments was incomplete. An average of 4.82 minutes (standard deviation = 3.17) was used to complete the tool. There was high interrater agreement for overall scores, with a multiple‐rater weighted κ of 83% (95% confidence interval = 76%‐89%). The interrater agreement was lower for the individual components. Both raters and trainees found the comments more useful than the numerical ratings. CONCLUSIONS: Our results support the use of the CLRS for facilitating feedback on the quality of consult letters to improve written‐communication competencies among geriatric medicine trainees. J Am Geriatr Soc 67:2157–2160, 2019 [ABSTRACT FROM AUTHOR]

Patients with Creutzfeldt-Jakob disease (CJD) may exhibit characteristic abnormalities on the electroencephalogram (EEG). However, these abnormalities have been associated with a number of cases of drug toxicity. We report a case of CJD-like syndrome associated with gabapentin. A 78-year-old man was hospitalized for recurrent falls. Three months prior to admission, gabapentin was prescribed to treat symptoms of trigeminal neuralgia. The patient subsequently presented with a two-month history of worsening gait abnormalities, negative myoclonus, and cognitive impairment. The EEG showed diffuse background slowing with larger amplitude delta discharges, which at times appeared triphasic, raising the possibility of CJD. The gait abnormalities and myoclonus resolved and the EEG normalized after the gabapentin was discontinued. Several cases of drug-induced CJD-like syndrome have been reported, mainly presenting with cognitive impairment, myoclonus, Parkinsonism, and EEG abnormalities. This patient may have been predisposed to adverse neurological effects from gabapentin owing to age, concurrent renal insufficiency, and cardiac disease. We concluded that it is imperative to include drug toxicity in the differential diagnosis of patients presenting with clinical manifestations and EEG findings suggestive of CJD, particularly in the setting of advanced age and comorbidities. [ABSTRACT FROM AUTHOR]

Introduction: Heart failure (HF) is common in older adults and standard therapy involves the use of multiple medications. We assessed the nature, frequency, and factors associated with adverse drug events (ADEs) associated with standard HF therapy among older adults greater than 75 years of age. The efficacy and predictors of ADEs were assessed in this patient population, as well., Methods: Systematic review using standardized databases including MEDLINE, Ageline, and CINAHL from January 1st 1988 to January 1st, 2010 and references from published literature. Randomized trials and studies with observational, cohort, and cross-sectional design were included. Two investigators independently selected the studies and extracted the data (kappa = 0.86)., Results: Twenty-five studies were identified. ADEs were reported in 13/23 (57%) studies. Syncope, bradycardia, and hypotension as a result of beta blockers occurred in greater frequency compared to younger populations. Spironolactone therapy resulted in increased rates of hyperkalemia, acute renal failure, and medication discontinuation. Factors associated with ADEs included advanced age, poor left ventricular function, and increasing New York Heart Association Class. Efficacy of beta blockers and ACE inhibitors appears to extend to the elderly population, but the magnitude of effect size is unclear. Very few studies reported associations between ADE and patients' comorbidities (4/13 studies, 31%) or functional status (3/13 studies, 23%)., Conclusion: ADEs in CHF therapy among the very elderly occurred at a greater frequency, but were generally poorly characterized in the literature despite a relatively common occurrence. Further studies are warranted.