Intelligent digital tools for screening of brain connectivity and dementia risk estimation in people affected by mild cognitive impairment: the AI-Mind clinical study protocol.

More than 10 million Europeans show signs of mild cognitive impairment (MCI), a transitional stage between normal brain aging and dementia stage memory disorder. The path MCI takes can be divergent; while some maintain stability or even revert to cognitive norms, alarmingly, up to half of the cases progress to dementia within 5 years. Current diagnostic practice lacks the necessary screening tools to identify those at risk of progression. The European patient experience often involves a long journey from the initial signs of MCI to the eventual diagnosis of dementia. The trajectory is far from ideal. Here, we introduce the AI-Mind project, a pioneering initiative with an innovative approach to early risk assessment through the implementation of advanced artificial intelligence (AI) on multimodal data. The cutting-edge AI-based tools developed in the project aim not only to accelerate the diagnostic process but also to deliver highly accurate predictions regarding an individual's risk of developing dementia when prevention and intervention may still be possible. AI-Mind is a European Research and Innovation Action (RIA H2020-SC1-BHC-06-2020, No. 964220) financed between 2021 and 2026. First, the AI-Mind Connector identifies dysfunctional brain networks based on high-density magneto- and electroencephalography (M/EEG) recordings. Second, the AI-Mind Predictor predicts dementia risk using data from the Connector, enriched with computerized cognitive tests, genetic and protein biomarkers, as well as sociodemographic and clinical variables. AI-Mind is integrated within a network of major European initiatives, including The Virtual Brain, The Virtual Epileptic Patient, and EBRAINS AISBL service for sensitive data, HealthDataCloud, where big patient data are generated for advancing digital and virtual twin technology development. AI-Mind's innovation lies not only in its early prediction of dementia risk, but it also enables a virtual laboratory scenario for hypothesis-driven personalized intervention research. This article introduces the background of the AI-Mind project and its clinical study protocol, setting the stage for future scientific contributions.

Functional, Clinical, and Sociodemographic Variables Associated with Risk of In-Hospital Mortality by COVID-19 in People over 80 Years Old.

OBJECTIVES: The objective is to assess the role of functional, clinical, and analytic parameters in predicting mortality in older patients hospitalized due to COVID-19. DESIGN: Cohort study with a mean follow-up of 12.8 days. SETTING: Public university hospital (Madrid, Spain). PARTICIPANTS: 499 patients 80 and above consecutively admitted to a Spanish public university hospital between 4 March 2020 and 16 May 2020. MEASUREMENTS: Mortality was the main outcome. Data of sociodemographic variables (age, sex, living), comorbidities, polypharmacy, functional status, date of hospital admission and length of stay was recorded. Clinical symptoms, laboratory and X-ray findings were collected at time of admission. For multivariant analysis, logistic regressions were performed to identify risk factors for death. RESULTS: Mean age was 86.7±4.4 with 37% of death. Mortality was associated with male gender [odds ratio (OR) 1.50; 95% confidence interval (CI) 1.01-2.24], with a 5-points increase on Barthel Index [OR 1.01 (95%CI 1.00-1.02)], higher Charlson Index score [OR 1.13 (95%CI 1.02-1.26)] and comorbidities [OR 1.28 (95%CI 1.06-1.53)], hyperpolipharmacy [OR 2.00 (95%CI 1.04-3.82)], unilateral pneumonia [OR 1.83 (95%CI 1.01-3.30)], higher levels of C-reactive protein [OR 1.09 (95%CI 1.06-1.12)] and creatine [OR 1.48 (95%CI 1.15-1.89)]. Higher oxygen levels were a protective factor [OR 0.92 (95%CI 0.89-0.95)]. CONCLUSIONS: Functional status, being male, a higher burden of comorbidities, hyperpolipharmacy, unilateral pneumonia and some laboratory parameters predict in-hospital mortality in this older population. The knowledge of these mortality risk factors should be used to improve the survival of older hospitalized patients.

Insulin resistance dysregulates CYP7B1 leading to oxysterol accumulation: a pathway for NAFL to NASH transition.

NAFLD is an important public health issue closely associated with the pervasive epidemics of diabetes and obesity. Yet, despite NAFLD being among the most common of chronic liver diseases, the biological factors responsible for its transition from benign nonalcoholic fatty liver (NAFL) to NASH remain unclear. This lack of knowledge leads to a decreased ability to find relevant animal models, predict disease progression, or develop clinical treatments. In the current study, we used multiple mouse models of NAFLD, human correlation data, and selective gene overexpression of steroidogenic acute regulatory protein (StarD1) in mice to elucidate a plausible mechanistic pathway for promoting the transition from NAFL to NASH. We show that oxysterol 7α-hydroxylase (CYP7B1) controls the levels of intracellular regulatory oxysterols generated by the "acidic/alternative" pathway of cholesterol metabolism. Specifically, we report data showing that an inability to upregulate CYP7B1, in the setting of insulin resistance, results in the accumulation of toxic intracellular cholesterol metabolites that promote inflammation and hepatocyte injury. This metabolic pathway, initiated and exacerbated by insulin resistance, offers insight into approaches for the treatment of NAFLD.

StarD5: an ER stress protein regulates plasma membrane and intracellular cholesterol homeostasis.

How plasma membrane (PM) cholesterol is controlled is poorly understood. Ablation of the gene encoding the ER stress steroidogenic acute regulatory-related lipid transfer domain (StarD)5 leads to a decrease in PM cholesterol content, a decrease in cholesterol efflux, and an increase in intracellular neutral lipid accumulation in macrophages, the major cell type that expresses StarD5. ER stress increases StarD5 expression in mouse hepatocytes, which results in an increase in accessible PM cholesterol in WT but not in StarD5-/- hepatocytes. StarD5-/- mice store higher levels of cholesterol and triglycerides, which leads to altered expression of cholesterol-regulated genes. In vitro, a recombinant GST-StarD5 protein transfers cholesterol between synthetic liposomes. StarD5 overexpression leads to a marked increase in PM cholesterol. Phasor analysis of 6-dodecanoyl-2-dimethylaminonaphthalene fluorescence lifetime imaging microscopy data revealed an increase in PM fluidity in StarD5-/- macrophages. Taken together, these studies show that StarD5 is a stress-responsive protein that regulates PM cholesterol and intracellular cholesterol homeostasis.

Mitochondrial oxysterol biosynthetic pathway gives evidence for CYP7B1 as controller of regulatory oxysterols.

The aim of this paper was to more completely study the mitochondrial CYP27A1 initiated acidic pathway of cholesterol metabolism. The mitochondrial CYP27A1 initiated pathway of cholesterol metabolism (acidic pathway) is known to synthesize two well-described vital regulators of cholesterol/lipid homeostasis, (25R)-26-hydroxycholesterol (26HC) and 25-hydroxycholesterol (25HC). Both 26HC and 25HC have been shown to be subsequently 7α-hydroxylated by Cyp7b1; reducing their regulatory abilities and furthering their metabolism to chenodeoxycholic acid (CDCA). Cholesterol delivery into the inner mitochondria membrane, where CYP27A1 is located, is considered the pathway's only rate-limiting step. To further explore the pathway, we increased cholesterol transport into mitochondrial CYP27A1 by selectively increased expression of the gene encoding the steroidogenic acute transport protein (StarD1). StarD1 overexpression led to an unanticipated marked down-regulation of oxysterol 7α-hydroxylase (Cyp7b1), a marked increase in 26HC, and the formation of a third vital regulatory oxysterol, 24(S)-hydroxycholesterol (24HC), in B6/129 mice livers. To explore the further metabolism of 24HC, as well as, 25HC and 26HC, characterizations of oxysterols and bile acids using three murine models (StarD1 overexpression, Cyp7b1-/-, Cyp27a1-/-) and human Hep G2 cells were conducted. This report describes the discovery of a new mitochondrial-initiated pathway of oxysterol/bile acid biosynthesis. Just as importantly, it provides evidence for CYP7B1 as a key regulator of three vital intracellular regulatory oxysterol levels.

[Oral anticoagulation therapy in the elderly population with atrial fibrillation. A review article]. / Anticoagulación en población anciana con fibrilación auricular no valvular. Artículo de revisión.

Aging is an important risk factor for patients with atrial fibrillation. The estimated prevalence of atrial fibrillation in patients aged ≥80 years is 9-10%, and is associated with a four to five fold increased risk of embolic stroke, and with an estimated increased stroke risk of 1.45-fold per decade in aging. Older age is also associated with an increased risk of major bleeding with oral anticoagulant therapy. This review will focus on the role of oral anticoagulation with new oral anticoagulants, non-vitamin K antagonist in populations with common comorbid conditions, including age, chronic kidney disease, coronary artery disease, on multiple medication, and frailty. In patients 75 years and older, randomised trials have shown new oral anticoagulants to be as effective as warfarin, or in some cases superior, with an overall better safety profile, consistently reducing rates of intracranial haemorrhages. Prior to considering oral anticoagulant therapy in an elderly frail patient, a comprehensive assessment should be performed to include the risks and benefits, stroke risk, baseline kidney function, cognitive status, mobility and fall risk, multiple medication, nutritional status assessment, and life expectancy.

Multidimensional intervention to improve the short-term prognosis of frail elderly patients discharged from a short-stay unit: A quasiexperimental study. / Intervención multidimensional que mejora el pronóstico a corto plazo entre los ancianos frágiles dados de alta desde una unidad de corta estancia: estudio cuasiexperimental.

OBJECTIVE: To study the effect of a multidimensional intervention on the prognosis at 30 days for frail elderly patients discharged from a short-stay unit. MATERIAL AND METHOD: A quasiexperimental study was conducted with a historical control cohort. We included frail patients (Identification of Seniors at Risk score≥2) 75 years of age or older, discharged from an short-stay unit over 2 months in 2013 (control group) and in 2016 (intervention group). An intervention was conducted based on the activation of resources, based on the deficiencies detected after an abbreviated geriatric assessment, in conjunction with Primary Care. The main endpoint was the presence of an adverse result (death or readmission for any cause or severe functional impairment) at 30 days of discharge. RESULTS: We included 137 (62.8%) patients in the intervention group and 81 (37.2%) in the control group. Eighteen (13.1%) patients in the intervention group and 29 (35.8%) in the control group presented an adverse event at 30 days. A multivariate analysis showed that the implementation of a multidimensional intervention was a protective factor for presenting an adverse event at 30 days of discharge (adjusted RR 0.40; 95% CI 0.23-0.68; P=.001). CONCLUSIONS: The implementation of an individual care plan for frail elderly patients, based on the activation of resources according to the deficiencies detected after an abbreviated geriatric assessment and in conjunction with Primary Care, could improve the results at 30 days of discharge from an short-stay unit.

Brain microbleeds: Epidemiology and clinical implications. / Microhemorragias cerebrales: epidemiología e implicaciones clínicas.

INTRODUCTION: Brain microbleeds (BMB) are haemosiderin deposits contained within macrophages, which are displayed as hypointense images in some T2-weighted magnetic resonance imaging sequences. There are still many questions to be answered about the pathophysiology and clinical relevance of BMB. DEVELOPMENT: We conducted a literature review of the main epidemiological, clinical, and anatomical pathology studies of BMB performed in the general population, in patients at risk of or already suffering from a vascular disease, and in patients with cognitive impairment. We analysed the prevalence of BMB, risk factors, and potential pathophysiological mechanisms and clinical implications. CONCLUSIONS: The prevalence of BMB is highly variable (3%-27% in the general population, 6%-80% in patients with vascular risk factors or vascular disease, and 16%-45% in patients with cognitive impairment). BMB are associated with ageing, Alzheimer disease (AD), and in particular haemorrhagic or ischaemic cerebrovascular disease. The pathological substrate of BMB is either lipohyalinosis (subcortical BMB) or cerebral amyloid angiopathy (lobar BMB). BMB exacerbate cognitive impairment, possibly through cortical-subcortical and intracortical disconnection, and increase the risk of death, mostly due to vascular causes. BMB also increase the risk of cerebral haemorrhage, particularly in patients with multiple lobar BMB (probable erebral amyloid angiopathy). Therefore, anticoagulant treatment may be contraindicated in these patients. In patients with lower risk of bleeding, the new oral anticoagulants and the combination of clinical and magnetic resonance imaging follow-up could be helpful in the decision-making process.

In-hospital mortality risk score for very old patients hospitalized with decompensated chronic heart failure.

OBJECTIVE: To derive a risk score to predict in-hospital mortality for very old patients with decompensated chronic heart failure (DCHF). METHODOLOGY: Retrospective cohort study that included patients ≥ 80 years admitted to a Geriatric Acute Care Unit with DCHF between January 2012 and December 2014. We analyzed 70 candidate risk factors and in-hospital mortality. We derived a risk model using multivariate logistic regression model and constructed a scale for scoring risk. We used bootstrapping techniques for the internal validation. RESULTS: We included 629 patients with mean age of 90 (SD5) years, 470 (73.1%) being women. Eighty-six (13.7%) patients died during the hospitalization. Factors included in the final risk model were NYHA class III-IV, severe functional dependence (Katz activities of daily living index < 2), infection as cause of exacerbation of heart failure, number of medications ≥ 8, albumin < 3 mg/dL, glomerular filtration rate < 60 mL/min, level of potassium in blood > 5.5 mEq/L and red blood cell distribution width (RDW) > 17%. In-hospital mortality in risk groups was 3.0, 4.6, 9.5, 15.1 and 36.3%, respectively. The area under ROC curve risk for score after bootstrapping was 0.77 (95%: CI 0.70-0.83). CONCLUSION: This risk score could be useful for stratifying risk for in-hospital mortality among very old patients admitted to hospital for DCHF.

[Consensus document on pneumococcal vaccination in adults at risk by age and underlying clinical conditions. 2017 Update]. / Consenso sobre la vacunación anti-neumocócica en el adulto por riesgo de edad y patología de base. Actualización 2017.

Invasive pneumococcal disease (IPD) and pneumococcal pneumonia (PP) represent an important health problem among aging adults and those with certain underlying pathologies and some diseases, especially immunosuppressed and some immunocompetent subjects, who are more susceptible to infections and present greater severity and worse evolution. Among the strategies to prevent IPD and PP, vaccination has its place, although vaccination coverage in this group is lower than desirable. Nowadays, there are 2 vaccines available for adults. Polysacharide vaccine (PPV23), used in patients aged 2 and older since decades ago, includes a greater number of serotypes (23), but it does not generate immune memory, antibody levels decrease with time, causes an immune tolerance phenomenon, and have no effect on nasopharyngeal colonization. PCV13 can be used from children 6 weeks of age to elderly and generates an immune response more powerful than PPV23 against most of the 13 serotypes included in it. In the year 2013 the 16 most directly related to groups of risk of presenting IPD publised a series of vaccine recommendations based on scientific evidence regarding anti-pneumococcal vaccination in adults with underlying pathologies and special conditions. A commitment was made about updating it if new scientific evidence became available. We present an exhaustive revised document focusing mainly in recommendation by age in which some more Scientific Societies have been involved.

[Clinical assessment and diagnostic tools]. / Evaluación clínica y herramientas diagnósticas.

The presence of cognitive impairment generates important changes in both affected individuals and their families and the health staff who must provide adequate care. Early identification of this alteration allows appropriate diagnosis and treatment and psychosocial and educational support, as well as the possibility of establishing care, life and financial plans. The interest of the scientific community in age-related cognitive alterations is demonstrated by the abundance of criteria and classifications. Obviously, there is a need to unify these criteria and implement longitudinal studies in order to reach reliable conclusions. Clinical assessment of the distinct cognitive domains should include careful history-taking and the use of diagnostic neuropsychological batteries. First, the ideal screening test would be one that could be administered in a few minutes, with a cut-off point that would identify patients requiring further assessment for correct diagnosis. The use of dynamic biomarkers is based on the hypothesis that they have a specific time-dependent model. These biomarkers include, firstly, markers of amyloidosis and, secondly, markers of neurodegeneration. Cognitive frailty is an emerging term inspired by a potential parallel with physical frailty syndrome. A subgroup of patients with cognitive impairment show a reduced capacity for recovery and functional decline that interact with physical frailty. The evidence suggests that cognitive status represents an important dimension of frailty syndrome.

[Breakthrough cancer pain in the elderly]. / Dolor irruptivo oncológico en el anciano.

Breakthrough pain is defined as an acute exacerbation of pain with rapid onset, short duration and moderate or high intensity, which occurs spontaneously or in connection with a predictable or unpredictable event despite there being stabilised and controlled baseline pain. However, there are doubts about the definition, terminology, epidemiology, and assessment of breakthrough pain, with no clear answers or consensus, especially in the elderly population. This non-systematic review summarises the most important aspects of breakthrough pain in the elderly, based on the limited publications there are in that population group.

[Diagnostic criteria. Benefits of early diagnosis]. / Criterios diagnósticos. Beneficios del diagnóstico precoz.

Almost 36 million persons live with dementia worldwide. This figure is set to double by 2030, with 66 million patients, and by 2050 there will be 116 million affected persons. Dementia has an economic impact on individuals and health services and affects the global economy. It is important to evaluate costs to plan social services and healthcare and to provide information on the cost-effectiveness of treatments. The economic cost of dementia was around 604 billion dollars in 2010 and estimates are obviously set to rise.

Frailty in elderly people with chronic kidney disease. / La fragilidad en el anciano con enfermedad renal crónica.

In recent years, the concept of frailty as a "state of pre-disability" has been widely accepted by those involved in the care of the elderly. Its importance lies not only in its high prevalence - more than 25% in people over 85 years of age - but it is also considered an independent risk factor of disability, institutionalisation and mortality amongst the elderly. The study of renal function is relevant in patients with major comorbidities. Studies have shown a significant association between chronic kidney disease and the development of adverse clinical outcomes such as heart disease, heart failure, end-stage renal disease, increased susceptibility to infections and greater functional impairment. Frailty can be reversed, which is why a study of frailty in patients with chronic kidney disease is of particular interest. This article aims to describe the association between ageing, frailty and chronic kidney disease in light of the most recent and relevant scientific publications.

[Clinical profile and 90-day mortality in centenarian patients attended in emergency departments]. / Perfil clínico y mortalidad a 90días de los pacientes centenarios atendidos en servicios de urgencias hospitalarios.

OBJECTIVES: To determine the clinical profile and to develop a model to predict 90-day mortality in centenarian patients attended in emergency departments (ED). METHODOLOGY: This was an observational, retrospective, multicentre cohort study including patients >99years attended in 5 ED in the Community of Madrid from January to December 2012. Demographic variables were recorded, as well as, comorbidities, cognitive, functional, social basal status, geriatric syndromes, acute episode, and hospital and social resources use, and 90-day mortality. RESULTS: The study included 209patients aged 101years (SD 1.7) of whom 161 (77.0%) were female. Sixty four (32.5%) had severe comorbidity (Charlson index≥3), 101 (49.8%) on multiple medication, 100 (52.6%) had cognitive impairment, 82 (42.3%) had severe functional dependence, 85 (40.7%) were institutionalised, and 190 (94.5%) had a geriatric syndrome. Dyspnoea (26.8%), followed by falls (12.4%) were the most common causes of attendance. One hundred and eighteen (56.5%) were admitted, and 58 out of 174 (33.3%) died in the first 90days. The model to predict 90-day overall mortality included male sex (OR 2.42 95% CI=0.97-6.04; P=.059), emergency care in the previous 3months (OR 4.08 95% CI=1.26-13.16; P=.019) and the hospitalization by index event (OR 8.63 95% CI=3.25-22.9; P<.001) and this model had an area under ROC curve of 0.776 (95% CI=0.70-0.85; P<.001). CONCLUSIONS: Centenarian patients attended in ED had a significant frailty and one in three cases died in the first 90days after being attended, and this was associated with male sex, emergency care in the previous 3months, and hospitalisation.

[Update on oncological pain in the elderly]. / Actualización del dolor oncológico en el anciano.

Pain is a prevalent symptom in cancer geriatric patients, appearing in up to 90% of patients with terminal cancer. This requires a multidimensional approach, as there is a high percentage of inappropriate assessments and treatments. Unrecognized or poorly treated pain in the geriatric population, especially in cancer patients, leads to the development of disabling symptoms such as depression, anxiety, isolation, sleep disturbances, and appetite, and very especially, loss of functional capacity and quality of life. In this review an analysis is made on the most relevant studies on the diagnosis and management of cancer pain in the geriatric population.