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While immune function is known to play a mechanistic role in Alzheimer's disease (AD), whether immune proteins in peripheral circulation influence the rate of amyloid-ß (Aß) progression - a central feature of AD - remains unknown. In the Baltimore Longitudinal Study of Aging, we quantified 942 immunological proteins in plasma and identified 32 (including CAT [catalase], CD36 [CD36 antigen], and KRT19 [keratin 19]) associated with rates of cortical Aß accumulation measured with positron emission tomography (PET). Longitudinal changes in a subset of candidate proteins also predicted Aß progression, and the mid- to late-life (20-year) trajectory of one protein, CAT, was associated with late-life Aß-positive status in the Atherosclerosis Risk in Communities (ARIC) study. Genetic variation that influenced plasma levels of CAT, CD36 and KRT19 predicted rates of Aß accumulation, including causal relationships with Aß PET levels identified with two-sample Mendelian randomization. In addition to associations with tau PET and plasma AD biomarker changes, as well as expression patterns in human microglia subtypes and neurovascular cells in AD brain tissue, we showed that 31 % of candidate proteins were related to mid-life (20-year) or late-life (8-year) dementia risk in ARIC. Our findings reveal plasma proteins associated with longitudinal Aß accumulation, and identify specific peripheral immune mediators that may contribute to the progression of AD pathophysiology.
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Enfermedad de Alzheimer , Péptidos beta-Amiloides , Biomarcadores , Progresión de la Enfermedad , Tomografía de Emisión de Positrones , Humanos , Péptidos beta-Amiloides/metabolismo , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/sangre , Enfermedad de Alzheimer/inmunología , Enfermedad de Alzheimer/genética , Masculino , Femenino , Anciano , Estudios Longitudinales , Tomografía de Emisión de Positrones/métodos , Biomarcadores/sangre , Biomarcadores/metabolismo , Proteoma/metabolismo , Persona de Mediana Edad , Encéfalo/metabolismo , Envejecimiento/metabolismo , Envejecimiento/inmunología , Anciano de 80 o más AñosRESUMEN
OBJECTIVES: Post-operative delirium (POD) affects up to 50% of cardiac surgery patients, with higher incidence in older adults. There is increasing need for screening tools that identify individuals most vulnerable to POD. Here, we examined the relationship between pre-operative olfaction and both incident POD and POD severity in patients undergoing cardiac surgery. We also examined cross-sectional relationships between baseline olfaction, cognition, and plasma neurofilament light (NfL). METHODS: Individuals undergoing cardiac surgery (n = 189; mean age = 70 years; 75% men) were enrolled in a clinical trial of cerebral autoregulation monitoring. At baseline, odor identification performance (Brief Smell Identification Test), cognitive performance, and plasma concentrations of NfL levels (Simoa™ NF-Light Assay) were measured. Delirium was assessed with the Confusion Assessment Method (CAM) or CAM-ICU, and delirium severity was assessed using the Delirium Rating Scale-Revised-98. The association of baseline olfaction, delirium incidence, and delirium severity was examined in regression models adjusting for age, duration of cardiopulmonary bypass, logistic European System for Cardiac Operative Risk Evaluation (EuroSCORE), and baseline cognition. RESULTS: Olfactory dysfunction was present in 30% of patients, and POD incidence was 44%. Pre-operative olfactory dysfunction was associated with both incident POD (OR = 3.17, p = 0.001) and greater severity of POD after cardiac surgery (OR = 3.94 p < 0.001) in models adjusted for age, duration of bypass, and a surgical risk score. The addition of baseline cognition attenuated the strength of the association, but it remained significant for incident POD (OR = 2.25, p = 0.04) and POD severity (OR 2.10, p = 0.04). Poor baseline olfaction was associated with greater baseline cognitive dysfunction (p < 0.001) and increased baseline plasma NfL concentrations (p = 0.04). Neither age, cognition, nor baseline NFL concentration modified the association of impaired olfaction and delirium outcomes. CONCLUSIONS: Olfactory assessment may be a useful pre-surgical screening tool for the identification of patients undergoing cardiac surgery at increased risk of POD. Identifying those at highest risk for severe delirium and poor cognitive outcomes following surgery would allow for earlier intervention and pre-operative rehabilitation strategies, which could ultimately impact the functional disability and morbidity associated with POD.
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Procedimientos Quirúrgicos Cardíacos , Delirio , Delirio del Despertar , Trastornos del Olfato , Masculino , Humanos , Anciano , Femenino , Delirio del Despertar/complicaciones , Olfato , Delirio/diagnóstico , Delirio/epidemiología , Delirio/etiología , Filamentos Intermedios , Complicaciones Posoperatorias/epidemiología , Procedimientos Quirúrgicos Cardíacos/efectos adversos , Factores de Riesgo , Cognición , Trastornos del Olfato/etiología , Trastornos del Olfato/complicacionesRESUMEN
BACKGROUND: Neurofilament light is a blood-based biomarker of neuroaxonal injury that can provide insight into perioperative brain vulnerability and injury. Prior studies have suggested that increased baseline and postoperative concentrations of neurofilament light are associated with delirium after noncardiac surgery, but results are inconsistent. Results have not been reported in cardiac surgery patients, who are among those at highest risk for delirium. We hypothesised that perioperative blood concentrations of neurofilament light (both baseline and change from baseline to postoperative day 1) are associated with delirium after cardiac surgery. METHODS: This study was nested in a trial of arterial blood pressure targeting during cardiopulmonary bypass using cerebral autoregulation metrics. Blood concentrations of neurofilament light were measured at baseline and on postoperative day 1. The primary outcome was postoperative delirium. Regression models were used to examine the associations between neurofilament light concentration and delirium and delirium severity, adjusting for age, sex, race, logistic European System for Cardiac Operative Risk Evaluation, bypass duration, and cognition. RESULTS: Delirium occurred in 44.6% of 175 patients. Baseline neurofilament light concentration was higher in delirious than in non-delirious patients (median 20.7 pg ml-1 [IQR 16.1-33.2] vs median 15.5 pg ml-1 [IQR 12.1-24.2], P<0.001). In adjusted models, greater baseline neurofilament light concentration was associated with delirium (odds ratio, 1.027; 95% confidence interval, 1.003-1.053; P=0.029) and delirium severity. From baseline to postoperative day 1, neurofilament light concentration increased by 42%, but there was no association with delirium. CONCLUSIONS: Baseline neurofilament light concentration, but not change from baseline to postoperative day 1, was associated with delirium after cardiac surgery.
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Procedimientos Quirúrgicos Cardíacos , Delirio , Humanos , Delirio/diagnóstico , Delirio/etiología , Filamentos Intermedios , Estudios Prospectivos , Encéfalo , Procedimientos Quirúrgicos Cardíacos/efectos adversos , Complicaciones Posoperatorias/diagnósticoRESUMEN
INTRODUCTION: Plasma proteomic analyses of unique brain atrophy patterns may illuminate peripheral drivers of neurodegeneration and identify novel biomarkers for predicting clinically relevant outcomes. METHODS: We identified proteomic signatures associated with machine learning-derived aging- and Alzheimer's disease (AD) -related brain atrophy patterns in the Baltimore Longitudinal Study of Aging (n = 815). Using data from five cohorts, we examined whether candidate proteins were associated with AD endophenotypes and long-term dementia risk. RESULTS: Plasma proteins associated with distinct patterns of age- and AD-related atrophy were also associated with plasma/cerebrospinal fluid (CSF) AD biomarkers, cognition, AD risk, as well as mid-life (20-year) and late-life (8-year) dementia risk. EFEMP1 and CXCL12 showed the most consistent associations across cohorts and were mechanistically implicated as determinants of brain structure using genetic methods, including Mendelian randomization. DISCUSSION: Our findings reveal plasma proteomic signatures of unique aging- and AD-related brain atrophy patterns and implicate EFEMP1 and CXCL12 as important molecular drivers of neurodegeneration. HIGHLIGHTS: Plasma proteomic signatures are associated with unique patterns of brain atrophy. Brain atrophy-related proteins predict clinically relevant outcomes across cohorts. Genetic variation underlying plasma EFEMP1 and CXCL12 influences brain structure. EFEMP1 and CXCL12 may be important molecular drivers of neurodegeneration.
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BACKGROUND: Proteins expressed by brain endothelial cells (BECs), the primary cell type of the blood-brain barrier, may serve as sensitive plasma biomarkers for neurological and neurovascular conditions, including cerebral small vessel disease. METHODS: Using data from the BLSA (Baltimore Longitudinal Study of Aging; n=886; 2009-2020), BEC-enriched proteins were identified among 7268 plasma proteins (measured with SomaScanv4.1) using an automated annotation algorithm that filtered endothelial cell transcripts followed by cross-referencing with BEC-specific transcripts reported in single-cell RNA-sequencing studies. To identify BEC-enriched proteins in plasma most relevant to the maintenance of neurological and neurovascular health, we selected proteins significantly associated with 3T magnetic resonance imaging-defined white matter lesion volumes. We then examined how these candidate BEC biomarkers related to white matter lesion volumes, cerebral microhemorrhages, and lacunar infarcts in the ARIC study (Atherosclerosis Risk in Communities; US multisite; 1990-2017). Finally, we determined whether these candidate BEC biomarkers, when measured during midlife, were related to dementia risk over a 25-year follow-up period. RESULTS: Of the 28 proteins identified as BEC-enriched, 4 were significantly associated with white matter lesion volumes (CDH5 [cadherin 5], CD93 [cluster of differentiation 93], ICAM2 [intracellular adhesion molecule 2], GP1BB [glycoprotein 1b platelet subunit beta]), while another approached significance (RSPO3 [R-Spondin 3]). A composite score based on 3 of these BEC proteins accounted for 11% of variation in white matter lesion volumes in BLSA participants. We replicated the associations between the BEC composite score, CDH5, and RSPO3 with white matter lesion volumes in ARIC, and further demonstrated that the BEC composite score and RSPO3 were associated with the presence of ≥1 cerebral microhemorrhages. We also showed that the BEC composite score, CDH5, and RSPO3 were associated with 25-year dementia risk. CONCLUSIONS: In addition to identifying BEC proteins in plasma that relate to cerebral small vessel disease and dementia risk, we developed a composite score of plasma BEC proteins that may be used to estimate blood-brain barrier integrity and risk for adverse neurovascular outcomes.
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Enfermedades de los Pequeños Vasos Cerebrales , Demencia , Humanos , Células Endoteliales/patología , Estudios Longitudinales , Encéfalo/patología , Biomarcadores/metabolismo , Enfermedades de los Pequeños Vasos Cerebrales/patología , Imagen por Resonancia MagnéticaRESUMEN
BACKGROUND: Neurofilament light is a marker of neuronal injury and can be measured in blood. Postoperative increases in neurofilament light have been associated with delirium after noncardiac surgery. However, few studies have examined the association of neurofilament light changes with postdischarge cognition in cardiac surgery patients, who are at highest risk for neuronal injury and cognitive decline. The authors hypothesized that increased neurofilament light (both baseline and change) would be associated with worse neuropsychological status up to 1 yr after cardiac surgery. METHODS: This observational study was nested in a trial of cardiac surgery patients, in which blood pressure during bypass was targeted using cerebral autoregulation monitoring. Plasma concentrations of neurofilament light were measured at baseline and postoperative day 1. Neuropsychological testing was performed at baseline, 1 month after surgery, and 1 yr after surgery. Primary outcomes were baseline and change from baseline in a composite z-score of all cognitive tests. RESULTS: Among 167 patients, cognitive outcomes were available in 80% (134 of 167) and 61% (102 of 167) at 1 month and 1 yr after surgery, respectively. The median baseline concentration of neurofilament light was 18.2 pg/ml (interquartile range, 13.4 to 28.1), and on postoperative day 1 was 28.5 pg/ml (interquartile range, 19.3 to 45.0). Higher baseline log neurofilament light was associated with worse baseline cognitive z-score (adjusted slope, -0.60; 95% CI, -0.90 to -0.30; P < 0.001), no change in z-score from baseline to 1 month (0.11; 95% CI, -0.19 to 0.41; P = 0.475), and improvement in z-score from baseline to 1 yr (0.56; 95% CI, 0.31 to 0.81; P < 0.001). Whereas some patients had an improvement in cognition at 1 yr and others a decline, an increase in neurofilament light from baseline to postoperative day 1 was associated with a greater decline in cognition at 1 yr. CONCLUSIONS: Higher baseline neurofilament light concentration was associated with worse baseline cognition but improvement in cognition at 1 yr. A postoperative increase in neurofilament light was associated with a greater cognitive decline at 1 yr.
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Cuidados Posteriores , Procedimientos Quirúrgicos Cardíacos , Procedimientos Quirúrgicos Cardíacos/efectos adversos , Cognición , Estudios de Cohortes , Humanos , Filamentos Intermedios , Alta del Paciente , Complicaciones Posoperatorias/etiología , Estudios ProspectivosRESUMEN
BACKGROUND: There is a need to adopt evidence-based approaches to discharge planning in the skilled nursing facility (SNF) short stay population. PURPOSE: This article describes implementation of the Reengineered Discharge (RED) process in SNFs and makes recommendations for its future implementation. METHODS: The methods included a pre- and postanalysis of an 18-month RED implementation with a contemporaneous comparison of 4 Midwestern SNFs randomly assigned to 2 different RED implementation strategies. The Standard facilities received less implementation than Enhanced facilities. RESULTS: Standard SNFs made more improvements and were more satisfied with the improved process than Enhanced SNFs. Field notes revealed that corporate willingness to make process changes impacted the Standard group's capacity for change; both groups were heavily influenced by external forces, and turnover was an impediment to RED implementation. CONCLUSION: This research revealed that discharge processes are similar across settings and that evidence-based programs such as RED can be adapted to the SNF setting.
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Personal de Enfermería/estadística & datos numéricos , Planificación de Atención al Paciente , Alta del Paciente/estadística & datos numéricos , Instituciones de Cuidados Especializados de Enfermería , Hospitalización , HumanosRESUMEN
Epstein-Barr virus (EBV) was the first human tumor virus discovered more than 50 years ago. EBV-associated lymphomagenesis is still a significant viral-associated disease as it involves a diverse range of pathologies, especially B-cell lymphomas. Recent development of high-throughput next-generation sequencing technologies and in vivo mouse models have significantly promoted our understanding of the fundamental molecular mechanisms which drive these cancers and allowed for the development of therapeutic intervention strategies. This review will highlight the current advances in EBV-associated B-cell lymphomas, focusing on transcriptional regulation, chromosome aberrations, in vivo studies of EBV-mediated lymphomagenesis, as well as the treatment strategies to target viral-associated lymphomas.
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Infecciones por Virus de Epstein-Barr/genética , Herpesvirus Humano 4/genética , Linfoma de Células B/genética , Animales , Aberraciones Cromosómicas , Infecciones por Virus de Epstein-Barr/patología , Infecciones por Virus de Epstein-Barr/terapia , Infecciones por Virus de Epstein-Barr/virología , Herpesvirus Humano 4/patogenicidad , Humanos , Linfoma de Células B/patología , Linfoma de Células B/terapia , Linfoma de Células B/virología , Ratones , Activación Transcripcional/genéticaRESUMEN
Interprofessional collaboration is the foundation of hospice service delivery. In the United States, hospice agencies are required to regularly convene interprofessional meetings during which teams review plans of care for the patients and families they serve. A small body of research suggests that team functioning could be significantly enhanced in hospice interprofessional meetings; however, systematic investigation of this possibility has been limited to date. The purpose of this qualitative study was to better understand the experiences and perspectives of hospice providers who regularly participate in interprofessional meetings as a first step toward improving teamwork in this setting. We interviewed 24 hospice providers and conducted a template analysis of qualitative data to identify barriers and facilitators to effective team functioning in interprofessional meetings. Participants recognised the ways meetings supported high-quality, holistic patient and family care but voiced frustrations over meeting inefficiencies, particularly in light of caseloads they perceived as overly demanding. Time constraints were often viewed as prohibiting the inclusion of interprofessional content and full participation of all team members. Findings suggest that modifications to interprofessional meetings such as standardising processes may enhance meeting efficiency and team functioning.
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Procesos de Grupo , Cuidados Paliativos al Final de la Vida/organización & administración , Relaciones Interprofesionales , Grupo de Atención al Paciente/organización & administración , Comunicación , Conducta Cooperativa , Humanos , Planificación de Atención al Paciente/organización & administración , Investigación Cualitativa , Estados Unidos , Compromiso Laboral , Carga de TrabajoRESUMEN
OBJECTIVE: We sought to determine the frequency with which hospice and palliative social workers encounter patients, family caregivers, and other clients at risk of suicide, and to discover the extent to which hospice and palliative social workers feel prepared to address issues related to suicide in their professional practice. METHOD: We conducted a cross-sectional survey of hospice and palliative social workers, recruiting a convenience sample of volunteer respondents through advertisements at professional conferences and listservs, and via social media accounts associated with national organizations, state hospice and palliative care associations, and individual healthcare professionals. RESULTS: Most respondents reported having worked with patients, family caregivers, or other clients who had exhibited warning signs of suicide during the previous year. Fewer respondents indicated that they had worked with patients and family members who had attempted or died by suicide. While the majority of respondents believed they possessed sufficient knowledge and skills to intervene effectively with individuals at risk of suicide, they indicated that additional education on this topic would be valuable for their professional practice. SIGNIFICANCE OF RESULTS: These study results suggest that suicide-related competencies are important in the practice of hospice and palliative social work. Future education and training efforts should include skill development in addition to knowledge building.
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Cuidados Paliativos al Final de la Vida/psicología , Trabajadores Sociales/psicología , Suicidio/psicología , Adulto , Estudios Transversales , Femenino , Cuidados Paliativos al Final de la Vida/métodos , Hospitales para Enfermos Terminales/organización & administración , Hospitales para Enfermos Terminales/estadística & datos numéricos , Humanos , Masculino , Persona de Mediana Edad , Psicometría/instrumentación , Psicometría/métodos , Psicometría/estadística & datos numéricos , Trabajadores Sociales/estadística & datos numéricos , Suicidio/estadística & datos numéricos , Encuestas y Cuestionarios , Recursos HumanosRESUMEN
OBJECTIVE: Although hospice agencies are required to provide informal caregivers (family or friends of the patient) with formal bereavement support when their loved one passes, most bereavement interventions lack standardization and remain untested. We employed the Dual Processing Model of Bereavement as a theoretical framework for assessing the potential of a secret Facebook group for bereaved hospice caregivers. METHOD: A mixed-methods approach was utilized to analyze online communication (posts and comments) in the secret Facebook group, and self-reported outcome measures on depression and anxiety were compared pre- and post-intervention. RESULTS: Sixteen caregivers participated in the secret Facebook group over a period of nine months. The majority of online talk was oriented to restoration, revealing abrupt and anticipated triggers that evoked feelings of loss. Caregivers also shared loss orientation through storytelling, sharing and giving advice, and encouraging others to manage the challenges of coping. Caregiver anxiety and depression were lower after the intervention. SIGNIFICANCE OF RESULTS: This pilot study provides insight into the use of a secret Facebook group to facilitate bereavement support to caregivers. Findings highlight the promise of Facebook for hospice bereavement support. Providers and researchers are encouraged to explore the positive outcomes associated with bereavement support.
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Aflicción , Cuidadores/psicología , Hospitales para Enfermos Terminales , Medios de Comunicación Sociales , Apoyo Social , Adaptación Psicológica , Ansiedad/prevención & control , Depresión/prevención & control , Depresión/psicología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Proyectos PilotoRESUMEN
PURPOSE: In August 2022, the Association of Social Work Boards released a long called for pass rate analysis that revealed significant disparities. While many states look to cease the requirement of the Bachelors, Masters, and Advanced Generalist exams in their licensure process, status quo bias leads to hesitancy to remove the requirement of the Clinical exam. METHOD: A critical review was undertaken to identify possible alternatives to the current multiple-choice competency-based exam which yielded three assessment formats (oral exams, portfolios, and performance assessment/simulations) and two alternatives (jurisprudence exams and provisional licensure). Informed by an Afrocentric lens, we undertook a social and racial policy analysis to examine alternative pathways for licensure from the perspective of a social work board member. We centered our analysis on the impacts on (1) Black social workers, who currently have the highest pass-rate disparities; (2) social workers whose primary language is not English, and (3) social workers with disabilities who have anecdotally reported difficulty with getting testing accommodations. We rated each alternative on four social equity analysis criteria of procedural fairness, access, quality, and outcomes. These ratings were computed into an overall rating for each alternative from equitable to inequitable. RESULTS: We found jurisprudence exams and provisional licensure have the best possibility of being equitable pathways to licensure, with potential impacts on the regulation of supervision and continuing education. CONCLUSION: Anti-racism and social justice as praxis require social work as a profession to divest from competency-based testing to eliminate racism in our own professional policies.
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Concesión de Licencias , Servicio Social , Humanos , Educación Continua , PolíticasRESUMEN
BACKGROUND: Although blood-based biomarkers have been identified as cost-effective and scalable alternatives to PET and CSF markers of neurodegenerative disease, little is known about how these biomarkers predict future brain atrophy and cognitive decline in cognitively unimpaired individuals. Using data from the Baltimore Longitudinal Study of Aging (BLSA), we examined whether plasma biomarkers of Alzheimer's disease (AD) pathology (amyloid-ß [Aß42/40], phosphorylated tau [pTau-181]), astrogliosis (glial fibrillary acidic protein [GFAP]), and neuronal injury (neurofilament light chain [NfL]) were associated with longitudinal brain volume loss and cognitive decline. Additionally, we determined whether sex, APOEε4 status, and plasma amyloid-ß status modified these associations. METHODS: Plasma biomarkers were measured using Quanterix SIMOA assays. Regional brain volumes were measured by 3T MRI, and a battery of neuropsychological tests assessed five cognitive domains. Linear mixed effects models adjusted for demographic factors, kidney function, and intracranial volume (MRI analyses) were completed to relate baseline plasma biomarkers to baseline and longitudinal brain volume and cognitive performance. RESULTS: Brain volume analyses included 622 participants (mean age ± SD: 70.9 ± 10.2) with an average of 3.3 MRI scans over 4.7 years. Cognitive performance analyses included 674 participants (mean age ± SD: 71.2 ± 10.0) with an average of 3.9 cognitive assessments over 5.7 years. Higher baseline pTau-181 was associated with steeper declines in total gray matter volume and steeper regional declines in several medial temporal regions, whereas higher baseline GFAP was associated with greater longitudinal increases in ventricular volume. Baseline Aß42/40 and NfL levels were not associated with changes in brain volume. Lower baseline Aß42/40 (higher Aß burden) was associated with a faster decline in verbal memory and visuospatial performance, whereas higher baseline GFAP was associated with a faster decline in verbal fluency. Results were generally consistent across sex and APOEε4 status. However, the associations of higher pTau-181 with increasing ventricular volume and memory declines were significantly stronger among individuals with higher Aß burden, as was the association of higher GFAP with memory decline. CONCLUSIONS: Among cognitively unimpaired older adults, plasma biomarkers of AD pathology (pTau-181) and astrogliosis (GFAP), but not neuronal injury (NfL), serve as markers of future brain atrophy and cognitive decline.
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Enfermedad de Alzheimer , Péptidos beta-Amiloides , Atrofia , Biomarcadores , Encéfalo , Disfunción Cognitiva , Proteínas tau , Humanos , Femenino , Masculino , Biomarcadores/sangre , Anciano , Atrofia/patología , Encéfalo/patología , Encéfalo/diagnóstico por imagen , Enfermedad de Alzheimer/sangre , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/diagnóstico por imagen , Péptidos beta-Amiloides/sangre , Disfunción Cognitiva/sangre , Disfunción Cognitiva/patología , Proteínas tau/sangre , Proteínas tau/líquido cefalorraquídeo , Estudios Longitudinales , Proteína Ácida Fibrilar de la Glía/sangre , Persona de Mediana Edad , Anciano de 80 o más Años , Proteínas de Neurofilamentos/sangre , Enfermedades Neurodegenerativas/sangre , Enfermedades Neurodegenerativas/diagnóstico por imagen , Enfermedades Neurodegenerativas/patología , Pruebas Neuropsicológicas , Imagen por Resonancia Magnética , Fragmentos de Péptidos/sangreRESUMEN
The choroid plexus (CP) is a vital brain structure essential for cerebrospinal fluid (CSF) production. Moreover, alterations in the CP's structure and function are implicated in molecular conditions and neuropathologies including multiple sclerosis, Alzheimer's disease, and stroke. Our goal is to provide the first characterization of the association between variation in the CP microstructure and macrostructure/volume using advanced magnetic resonance imaging (MRI) methodology, and blood-based biomarkers of Alzheimer's disease (Aß42/40 ratio; pTau181), neuroinflammation and neuronal injury (GFAP; NfL). We hypothesized that plasma biomarkers of brain pathology are associated with disordered CP structure. Moreover, since cerebral microstructural changes can precede macrostructural changes, we also conjecture that these differences would be evident in the CP microstructural integrity. Our cross-sectional study was conducted on a cohort of 108 well-characterized individuals, spanning 22-94 years of age, after excluding participants with cognitive impairments and non-exploitable MR imaging data. Established automated segmentation methods were used to identify the CP volume/macrostructure using structural MR images, while the microstructural integrity of the CP was assessed using our advanced quantitative high-resolution MR imaging of longitudinal and transverse relaxation times (T1 and T2). After adjusting for relevant covariates, positive associations were observed between pTau181, NfL and GFAP and all MRI metrics. These associations reached significance (p<0.05) except for CP volume vs. pTau181 (p=0.14), CP volume vs. NfL (p=0.35), and T2 vs. NFL (p=0.07). Further, negative associations between Aß42/40 and all MRI metrics were observed but reached significance only for Aß42/40 vs. T2 (p=0.04). These novel findings demonstrate that reduced CP macrostructural and microstructural integrity is positively associated with blood-based biomarkers of AD pathology, neurodegeneration/neuroinflammation and neurodegeneration. Degradation of the CP structure may co-occur with AD pathology and neuroinflammation ahead of clinically detectable cognitive impairment, making the CP a potential structure of interest for early disease detection or treatment monitoring.
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Infections have been associated with the incidence of Alzheimer disease and related dementias, but the mechanisms responsible for these associations remain unclear. Using a multicohort approach, we found that influenza, viral, respiratory, and skin and subcutaneous infections were associated with increased long-term dementia risk. These infections were also associated with region-specific brain volume loss, most commonly in the temporal lobe. We identified 260 out of 942 immunologically relevant proteins in plasma that were differentially expressed in individuals with an infection history. Of the infection-related proteins, 35 predicted volumetric changes in brain regions vulnerable to infection-specific atrophy. Several of these proteins, including PIK3CG, PACSIN2, and PRKCB, were related to cognitive decline and plasma biomarkers of dementia (Aß42/40, GFAP, NfL, pTau-181). Genetic variants that influenced expression of immunologically relevant infection-related proteins, including ITGB6 and TLR5, predicted brain volume loss. Our findings support the role of infections in dementia risk and identify molecular mediators by which infections may contribute to neurodegeneration.
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Methicillin-resistant Staphylococcus aureus (MRSA) is a pathogen empirically covered in pulmonary infections. Limited studies evaluate the relationship between the MRSA PCR nasal swab assays and clinically diagnosed ventilator-associated pneumonia (VAP), lung abscess, and empyema. This retrospective, single-center study included 161 patients, which aimed to validate the clinical utility of MRSA PCR nasal swabs in VAP, lung abscess, and empyema through sensitivity, specificity, positive predictive value (PPV), and negative predicative value (NPV) analysis. VAP had a 100% sensitivity, 89% specificity, 67% PPV, and 100% NPV. Lung abscess had a 0% sensitivity, 90% specificity, 0% PPV, 90% NPV. Empyema had a 80% sensitivity, 84% specificity, 42% PPV, and 97% NPV. The study results demonstrate that the MRSA PCR nasal swab assay has the potential to be a vital tool in de-escalating antimicrobial therapy in VAP, lung abscess, and empyema.
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Empiema , Absceso Pulmonar , Staphylococcus aureus Resistente a Meticilina , Neumonía Asociada al Ventilador , Infecciones Estafilocócicas , Humanos , Staphylococcus aureus Resistente a Meticilina/genética , Neumonía Asociada al Ventilador/diagnóstico , Neumonía Asociada al Ventilador/tratamiento farmacológico , Absceso Pulmonar/diagnóstico , Estudios Retrospectivos , Reacción en Cadena de la Polimerasa/métodos , Infecciones Estafilocócicas/diagnósticoRESUMEN
(1) Background: Despite the existence of well-established, CSF-based biomarkers such as amyloid-ß and phosphorylated-tau, the pathways involved in the pathophysiology of Alzheimer's disease (AD) remain an active area of research. (2) Methods: We measured 3072 proteins in CSF samples of AD-biomarker positive mild cognitive impairment (MCI) participants (n = 38) and controls (n = 48), using the Explore panel of the Olink proximity extension assay (PEA). We performed group comparisons, association studies with diagnosis, age, and APOE ε4 status, overrepresentation analysis (ORA), and gene set enrichment analysis (GSEA) to determine differentially expressed proteins and dysregulated pathways. (3) Results: GSEA results demonstrated an enrichment of granulocyte-related and chemotactic pathways (core enrichment proteins: ITGB2, ITGAM, ICAM1, SELL, SELP, C5, IL1A). Moreover, some of the well-replicated, differentially expressed proteins in CSF included: ITGAM, ITGB2, C1QA, TREM2, GFAP, NEFL, MMP-10, and a novel tau-related marker, SCRN1. (4) Conclusion: Our results highlight the upregulation of neuroinflammatory pathways, especially chemotactic and granulocyte recruitment in CSF of early AD patients.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Humanos , Proyectos Piloto , Proteínas tau/líquido cefalorraquídeo , Proteómica , Enfermedad de Alzheimer/genética , Disfunción Cognitiva/líquido cefalorraquídeo , Péptidos beta-Amiloides/líquido cefalorraquídeo , Biomarcadores/líquido cefalorraquídeo , Fragmentos de Péptidos , Proteínas del Tejido NerviosoRESUMEN
OBJECTIVE: White matter damage is a feature of Alzheimer's disease, yet little is known about how facets of the Alzheimer's disease process relate to key features of white matter structure. We examined the association of Alzheimer's disease (Aß42/40 ratio; pTau181), neuronal injury (NfL), and reactive astrogliosis (GFAP) biomarkers with MRI measures of myelin content and axonal density. METHODS: Among cognitively normal participants in the BLSA and GESTALT studies who received MRI measures of myelin content (defined by myelin water fraction [MWF]) and axonal density (defined by neurite density index [NDI]), we quantified plasma levels of Aß42 , Aß40 , pTau181, NfL, and GFAP. Linear regression models adjusted for demographic variables were used to relate these plasma biomarker levels to the MRI measures. RESULTS: In total, 119 participants received MWF imaging (age: 56 [SD 21]), of which 43 received NDI imaging (age: 50 [SD 18]). We found no relationship between plasma biomarkers and total brain myelin content. However, secondary analysis found higher GFAP was associated with lower MWF in the temporal lobes (ß = -0.13; P = 0.049). Further, higher levels of NfL (ß = -0.22; P = 0.009) and GFAP (ß = -0.29; P = 0.002) were associated with lower total brain axonal density. Secondary analyses found lower Aß42/40 ratio and higher pTau181 were also associated with lower axonal density, but only in select brain regions. These results remained similar after additionally adjusting for cardiovascular risk factors. INTERPRETATION: Plasma biomarkers of neuronal injury and astrogliosis are associated with reduced axonal density and region-specific myelin content. Axonal loss and demyelination may co-occur with neurodegeneration and astrogliosis ahead of clinically meaningful cognitive decline.
Asunto(s)
Enfermedad de Alzheimer , Vaina de Mielina , Humanos , Persona de Mediana Edad , Gliosis , Imagen por Resonancia Magnética/métodos , Envejecimiento , BiomarcadoresRESUMEN
Disulfide analogs of the alcohol sobriety medication disulfiram (Antabuse®) were evaluated for antimicrobial activity. Structure-activity relationship analyses of MIC data obtained for methicillin-resistant Staphylococcus aureus (MRSA) and other pathogenic organisms revealed correlations between the lipophilicity and bulkiness of the substituents. Analogs conferring optimal anti-MRSA activity contained S-octyl disulfides and either N,N-dimethyl- or N-pyrrolidine dithiocarbamate substituents. Additional testing revealed that both disulfiram and its S-octyl derivative are capable of sensitizing S. aureus to the bactericidal effects of fosfomycin. Mechanistic studies established that the compounds decrease intracellular levels of the fosB cofactor bacillithiol through a thiol-disulfide exchange reaction. The increased fosfomycin susceptibility in S. aureus was thereby attributed to a depleted cellular bacillithiol pool available for inactivation by fosB.
Asunto(s)
Antiinfecciosos/farmacología , Disulfiram/farmacología , Farmacorresistencia Bacteriana/efectos de los fármacos , Fosfomicina/farmacología , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Proteínas Proto-Oncogénicas c-fos/metabolismo , Proteínas Bacterianas/metabolismo , Cisteína/análogos & derivados , Cisteína/metabolismo , Glucosamina/análogos & derivados , Glucosamina/metabolismo , Humanos , Staphylococcus aureus Resistente a Meticilina/metabolismo , Pruebas de Sensibilidad Microbiana/métodos , Infecciones Estafilocócicas/tratamiento farmacológico , Compuestos de Sulfhidrilo/farmacologíaRESUMEN
Background and Objectives: The assessment of biomarkers in selecting patients with idiopathic normal pressure hydrocephalus (iNPH) for shunt surgery has been limited to small cohort studies and those with limited follow-up. We assessed the potential for CSF biomarkers in predicting immediate response to CSF tap test (TT) and long-term response after shunt surgery. Methods: CSF was obtained from patients with iNPH referred for CSF TT after baseline assessment of cognition and gait. CSF neurofilament light (NfL), ß-amyloid 42 (Aß1-42), ß-amyloid 40 (Aß1-40), total tau (tTau), and phosphorylated tau 181 (pTau181) and leucine-rich alpha-2-glycoprotein-1 (LRG1) were measured by ELISA. The ability of these measures to predict immediate improvement following CSF TT and long-term improvement following shunt surgery was compared by univariate and adjusted multivariate regression. Results: Lower NfL, pTau181, tTau, and Aß1-40 were individually predictive of long-term improvement in gait outcomes after shunt surgery. A multivariate model of these biomarkers and MRI Evans index, adjusted for age, improved prediction (area under the receiver operating curve 0.76, 95% confidence interval 0.66-0.86). tTau, pTau181, and Aß1-40 levels were statistically different in those whose gait improved after CSF TT compared with those who did not. Using a multivariate model, combining these markers with Evans index and transependymal flow did not significantly improve prediction of an immediate response to CSF TT. Discussion: A combination of CSF biomarkers can predict improvement following shunt surgery for iNPH. However, these measures only modestly discriminate responders from nonresponders following CSF TT. The findings further suggest that abnormal CSF biomarkers in nonresponders may represent comorbid neurodegenerative pathology or a predegenerative phase that presents with an iNPH phenotype.