Targeting the Hallmarks of Aging with Vitamin D: Starting to Decode the Myth.

Aging is the result of several complex and multifactorial processes, where several agents contribute to an increased intrinsic vulnerability and susceptibility to age-related diseases. The hallmarks of aging are a set of biological mechanisms that are finely regulated and strictly interconnected, initiating or contributing to biological changes and anticipating several age-related diseases. The complex network of cellular and intercellular connections between the hallmarks might represent a possible target for the research of agents with pleiotropic effects. Vitamin D (VitD) is known to have a positive impact not only on muscle and bone health but also on several extra-skeletal districts, due to the widespread presence of Vitamin D Receptors (VDRs). VitD and VDR could be molecules potentially targeting the hallmarks of the aging network. To date, evidence about the potential effects of VitD on the hallmarks of aging is scarce in humans and mainly based on preclinical models. Although underpowered and heterogeneous, in-human studies seem to confirm the modulatory effect of VitD on some hallmarks of aging and diseases. However, more investigations are needed to clarify the pleiotropic effects of VitD and its impact on the hallmark of aging, hopefully highlighting the courses for translational applications and potential clinical conclusions.

Multidimensional Oncological Frailty Scale (MOFS): A New Quick-To-Use Tool for Detecting Frailty and Stratifying Risk in Older Patients with Cancer-Development and Validation Pilot Study.

BACKGROUND: Frailty detection with comprehensive geriatric assessment (CGA) is of pivotal importance in older patients with cancer to avoid over- or under-treatment and to detect those at increased risk for poor outcomes. Several tools have been developed to capture the complexity of frailty, but only a few were explicitly conceived for older adults with cancer. The study aimed at developing and validating a multidimensional, easy-to-use diagnostic tool for early-risk stratification in patients with cancer, called the Multidimensional Oncological Frailty Scale (MOFS). METHODS: In this single-center prospective study, we consecutively enrolled 163 older women (age ≥ 75 years) with breast cancer, screened with a G8 score ≤ 14 during the outpatient preoperative evaluation at our breast centre, as the development cohort. Seventy patients with different types of cancer admitted to our OncoGeriatric Clinic served as the validation cohort. Using stepwise linear regression analysis, we evaluated the relationship between Multidimensional Prognostic Index (MPI) and CGA items, and, finally, realized a screening tool based on the combination of the significant variables. RESULTS: The mean age of the study population was 80.4 ± 5.8 years, while the mean age of the validation cohort was 78.6 ± 6.6 years [42 women (60%)]. A composite model of the Clinical Frailty Scale, G8, and hand grip strength test showed a strong correlation with MPI (R= -0.712, p < 0.001). The MOFS accuracy in the prediction of mortality was optimal in both the development and the validation cohorts (AUC 0.82 and 0.87; p < 0.001 and 0.003, respectively). CONCLUSION: MOFS represents a new, accurate, quick-to-use frailty screening tool for stratifying the risk of mortality in geriatric cancer patients.

The Free Triiodothyronine/Free Thyroxine Ratio Is Associated with Frailty in Older Adults: A Longitudinal Multisetting Study.

Background: Various models have been proposed to predict frailty, including those based on clinical criteria and phenotypes. However, a simple biomarker associated with frailty has been not yet identified. The aim of this study is to evaluate the relationship between free triiodothyronine (fT3)/free thyroxine (fT4) ratio value and the degree of frailty among three different cohorts of older individuals: (1) acutely ill hospitalized patients, (2) nursing-home (NH) residents, and (3) home-dwelling centenarians. Methods: We performed a secondary analysis of de-identified patient-level data from two prospective observational studies on acutely hospitalized older patients (Geriatric Acute Unit [GAU]), and home-dwelling centenarians (CENT), and a retrospective-prospective observational study on older NH residents. Demographic characteristics, along with a 30-items Frailty Index (FI) and serum thyrotropin, fT3 and fT4 measurements were obtained. Results: Six hundred fifteen individuals (aged 86.4 ± 8.9 years; 55.1% females) were included in the study, including 298 (48.5%) GAU, 250 (40.6%) NH, and 67 (10.9%) CENT. A significant inverse relationship between fT3/fT4 ratio and FI values was observed (ρs = -0.17 [confidence interval; CI: -0.092 to 0.252], p < 0.001), and this was confirmed by logistic multivariate analysis (ß = -0.44, odds ratio [OR]: 0.64 [CI: 0.47-0.87], p < 0.001) (after adjustment for age, sex, and cohorts). Moreover, a progressively decreased mortality risk was associated with rising fT3/fT4 ratio (OR 0.60 [CI: 0.44-0.80] ß = -0.51, p < 0.001]. Conclusions: The fT3/fT4 ratio value was inversely correlated with frailty degree and mortality risk in a large cohort of older individuals, including centenarians, regardless of their sex and clinical condition. fT3/fT4 ratio value could represent an easily measured independent biochemical marker of frailty degree in older people.

Determinants of 1-Year Adverse Event Requiring Re-Hospitalization in COVID-19 Oldest Old Survivors.

The incidence of "Long COVID" syndrome appears to be increasing, particularly in the geriatric population. At present, there are few data regarding the relationship between long COVID and the risk of re-hospitalization in the oldest old survivors. Patients older than 80 years consecutively hospitalized for COVID-19 in our tertiary care hospital were enrolled and followed after discharge in a 12-month ambulatory program. A comprehensive geriatric assessment (CGA), including functional capabilities and physical and cognitive performances, was performed at 6-month follow-up. Frailty degree was assessed using a 30-item frailty index. The re-hospitalization rate was assessed at 12-month follow-up through a computerized archive and phone interviews. Out of 100 patients discharged after hospitalization for COVID-19 (mean [SD] age 85 [4.0] years), 24 reported serious adverse events requiring re-hospitalization within 12 months. The most frequent causes of re-hospitalization were acute heart failure (HF), pneumonia and bone fracture (15.3% each). By multivariate logistic analysis, after adjustment for potential confounders, history of chronic HF [aOR: 3.00 (CI 95%: 1.10-8.16), p = 0.031] or chronic renal failure [aOR: 3.83 (CI 95%: 1.09-13.43), p = 0.036], the burden of comorbidity [(CIRSc) aOR: 1.95 (CI 95%: 1.28-2.97), p = 0.002] and frailty [aOR: 7.77 (CI 95%: 2.13-28.27), p = 0.002] resulted as independent predictors of re-hospitalization. One-fourth of the oldest old patients previously hospitalized for COVID-19 suffered from adverse events requiring re-hospitalization, two-thirds of them within three months after discharge. Frailty, the burden of comorbidity, history of chronic HF or chronic renal failure, but not COVID-19 disease severity, independently predicted re-hospitalization.

Determinants of Cause-Specific Mortality and Loss of Independence in Older Patients following Hospitalization for COVID-19: The GeroCovid Outcomes Study.

Hospitalization for acute SARS-CoV-2 infection confers an almost five-fold higher risk of post-discharge, all-cause mortality compared to controls from the general population. A negative impact on the functional autonomy of older patients, especially in cases of severe disease and prolonged hospitalization, has been recently described. However, little is known about the determinants of cause-specific mortality and loss of independence (LOI) in the activities of daily living (ADL) following COVID-19 hospitalization. Thus, the current prospective, multicenter study is aimed at identifying the determinants of post-discharge cause-specific mortality and the loss of autonomy in at least one ADL function. Older patients hospitalized for a SARS-CoV-2 infection were consecutively enrolled in an e-Registry from 1 March 2020, until 31 December 2020. After at least six months from discharge, patients were extensively re-evaluated according to a common protocol at the outpatient clinic of eight tertiary care Italian hospitals. Of 193 patients [109 (56.4%) men, mean age 79.9 ± 9.1 years], 43 (22.3%) died during follow-up. The most common causes of death were cardiovascular diseases (46.0%), respiratory failure (26.5%), and gastrointestinal and genitourinary diseases (8.8% each). Pre-morbid ADLs qualified as an independent mortality risk factor [adjusted HR 0.77 (95%CI: 0.63-0.95)]. Of 132 patients, 28 (21.2%) lost their independence in at least one ADL. The adjusted risk of LOI declined with a lower frailty degree [aOR 0.03 (95%CI: 0.01-0.32)]. In conclusion, at long-term follow-up after hospitalization for acute SARS-CoV-2 infection, more than 40% of older patients died or experienced a loss of functional independence compared to their pre-morbid condition. Given its high prevalence, the loss of functional independence after hospitalization for COVID-19 could be reasonably included among the features of the "Long COVID-19 syndrome" of older patients.

Astrogliosis in aging and Parkinson's disease dementia: a new clinical study with 11C-BU99008 PET.

The role of astrogliosis in the pathology of brain aging and neurodegenerative diseases has recently drawn great attention. Imidazoline-2 binding sites represent a possible target to map the distribution of reactive astrocytes. In this study, we use 11C-BU99008, an imidazoline-2 binding sites-specific PET radioligand, to image reactive astrocytes in vivo in healthy controls and patients with established Parkinson's disease dementia. Eighteen healthy controls (age: 45-78 years) and six patients with Parkinson's disease dementia (age: 64-77 years) had one 11C-BU99008 PET-CT scan with arterial input function. All subjects underwent one 3 T MRI brain scan to facilitate the analysis of the PET data and to capture individual cerebral atrophy. Regional 11C-BU99008 volumes of distribution were calculated for each subject by the two-tissue compartmental modelling. Positive correlations between 11C-BU99008 volumes of distribution values and age were found for all tested regions across the brain within healthy controls (P < 0.05); furthermore, multiple regression indicated that aging affects 11C-BU99008 volumes of distribution values in a region-specific manner. Independent samples t-test indicated that there was no significant group difference in 11C-BU99008 volumes of distribution values between Parkinson's disease dementia (n = 6; mean age = 71.97 ± 4.66 years) and older healthy controls (n = 9; mean age = 71.90 ± 5.51 years). Our data set shows that astrogliosis is common with aging in a region-specific manner. However, in this set-up, 11C-BU99008 PET cannot differentiate patients with Parkinson's disease dementia from healthy controls of similar age.

Pitfalls of Early Systemic Corticosteroids Home Therapy in Older Patients with COVID-19 Pneumonia.

Corticosteroids have been widely used for acute respiratory distress syndrome (ARDS), but their role in the early phase of SARS-CoV-2 infection is controversial. Our study aimed to determine the effectiveness of early corticosteroid therapy (ECT) in preventing the progression of disease, reducing the escalation of care and improving clinical outcome in older patients hospitalized for COVID-19 pneumonia. A total of 90 subjects (47.7% women; mean age = 82.3 ± 6.7 years) were enrolled. ECT was administered to 33 out of 90 patients before the hospitalization. At admission, no difference was detected in median SOFA score (2, IQR:2 vs. 2, IQR: 2). We found a significant difference in mean PaO2/FiO2 ratio during the first week of hospitalization between ECT patients and controls (F = 5.49, p = 0.002) and in mean PaO2/FiO2 ratio over time (F = 6.94, p < 0.0001). We detected no-significant differences in terms of in-hospital mortality and transfer to ICU between ECT patients and controls (27.1% vs. 22.8%, respectively, p = 0.63). ECT was associated with worse clinical outcomes, showing no benefit in attenuating the progression of the disease or reducing the escalation of care. These findings are crucial given the current pandemic, and further studies are needed to provide additional data on the optimal timing of initiating corticosteroid treatment.

Relationship between astrocyte reactivity, using novel 11C-BU99008 PET, and glucose metabolism, grey matter volume and amyloid load in cognitively impaired individuals.

Post mortem neuropathology suggests that astrocyte reactivity may play a significant role in neurodegeneration in Alzheimer's disease. We explored this in vivo using multimodal PET and MRI imaging. Twenty subjects (11 older, cognitively impaired patients and 9 age-matched healthy controls) underwent brain scanning using the novel reactive astrocyte PET tracer 11C-BU99008, 18F-FDG and 18F-florbetaben PET, and T1-weighted MRI. Differences between cognitively impaired patients and healthy controls in regional and voxel-wise levels of astrocyte reactivity, glucose metabolism, grey matter volume and amyloid load were explored, and their relationship to each other was assessed using Biological Parametric Mapping (BPM). Amyloid beta (Aß)-positive patients showed greater 11C-BU99008 uptake compared to controls, except in the temporal lobe, whilst further increased 11C-BU99008 uptake was observed in Mild Cognitive Impairment subjects compared to those with Alzheimer's disease in the frontal, temporal and cingulate cortices. BPM correlations revealed that regions which showed reduced 11C-BU99008 uptake in Aß-positive patients compared to controls, such as the temporal lobe, also showed reduced 18F-FDG uptake and grey matter volume, although the correlations with 18F-FDG uptake were not replicated in the ROI analysis. BPM analysis also revealed a regionally-dynamic relationship between astrocyte reactivity and amyloid uptake: increased amyloid load in cortical association areas of the temporal lobe and cingulate cortices was associated with reduced 11C-BU99008 uptake, whilst increased amyloid uptake in primary motor and sensory areas (in which amyloid deposition occurs later) was associated with increased 11C-BU99008 uptake. These novel observations add to the hypothesis that while astrocyte reactivity may be triggered by early Aß-deposition, sustained pro-inflammatory astrocyte reactivity with greater amyloid deposition may lead to astrocyte dystrophy and amyloid-associated neuropathology such as grey matter atrophy and glucose hypometabolism, although the evidence for glucose hypometabolism here is less strong.

A Randomized, Open-Label Study to Assess Efficacy of Weekly Assumption of Cholecalciferol versus Calcifediol in Older Patients with Hypovitaminosis D.

The aim of this single-center, open-label, randomized controlled study was to evaluate which formulation of vitamin D-between cholecalciferol and calcifediol-is most effective in the treatment of hypovitaminosis D in older adults. Demographic characteristics, clinical history, and comprehensive geriatric assessment were recorded at admission. Eligible patients were randomly assigned an equivalent vitamin D supplement, either with cholecalciferol or calcifediol, from the time of hospital admission to three months after discharge. Among the 140 older patients included (mean age 83 ± 6.6 years, 57.8% females), 69 received cholecalciferol and 71 received calcifediol. The mean plasma values of 25-hydroxyvitamin D3 (25OH-vitamin D3) found at the time of enrollment were 16.8 ± 9.9 ng/mL in patients receiving cholecalciferol and 18.8 ± 13.3 ng/mL in those treated with calcifediol (p = 0.31). At the three month follow-up, the mean concentration of 25OH-vitamin D3 was significantly higher in patients treated with calcifediol than in those receiving cholecalciferol (30.7 ± 8.4 vs. 45.4 ± 9.8 ng/mL, respectively; p < 0.001). Supplementation with either cholecalciferol or calcifediol effectively results in reaching the optimal circulating values of 25OH-vitamin D3 in older patients suffering from hypovitaminosis D. However, supplementation with calcifediol led to average circulating values of 25OH-vitamin D3 that were significantly higher (over 50%) than those obtained with cholecalciferol.

Different glomerular filtration rate estimating formula for prescribing DOACs in oldest patients: appropriate dosage and bleeding risk. Post hoc analysis of a prospective cohort.

BACKGROUND: Direct oral anticoagulants (DOACs) pharmacokinetics depends on estimated glomerular filtration rate (eGFR), whose estimation is crucial for optimal risk/benefit balance. AIMS: To assess the concordance among different eGFR formulas and the potential impact on DOACs prescription appropriateness and bleeding risk in oldest hospitalized patients. METHODS: Post hoc analysis of a single-centre prospective cohort study. eGFR was calculated by creatinine-based (MDRD, CKD-EPICr, BIS1) and creatinine-cystatin-C-based (CKD-EPIComb and BIS2) formulas. Patients were stratified according to eGFR [severely depressed (SD) 15-29; moderately depressed (MD) 30-49; preserved/mildly depressed (PMD): ≥ 50 ml/min/1.73 m2]. Concordance between the different equations was assessed by Cohen's kappa coefficient. RESULTS: Among AF patients, 841 (59.2% women, mean age 85.9 ± 6.5 years) received DOACs. By CKD-EPICr equation, 135 patients were allocated in the SD, 255 in the MD and 451 in the PMD group. The concordance was excellent only between BIS 2 and CKD-EPIComb and MDRD and CKD-EPICr, while was worse (from good to poor) between the other formulas. Indeed, by adding cystatin-C almost over 1/3 of the patients were reallocated to a worse eGFR class. Bleeding prevalence increased by 2-3% in patients with discordant eGFR between formulas, reallocated to a worse chronic kidney disease (CKD) stage, although without reaching statistical significance. CKD-EPIComb resulted the best predictor of bleeding events (AUROC 0.71, p = 0.03). DISCUSSION: This study highlights the variability in CKD staging according to different eGFR formulas, potentially determining inappropriate DOACs dosing. Although the cystatin-C derived CKDEPIComb equation is the most accurate for stratifying patients, BIS1 may represent a reliable alternative.

Management of Older Outpatients during the COVID-19 Pandemic: The GeroCovid Ambulatory Study.

OBJECTIVES: The GeroCovid Study is a multi-setting, multinational, and multi-scope registry that includes the GeroCovid home and outpatients' care cohort. The present study aims to evaluate whether outpatient and home care services with remote monitoring and consultation could mitigate the impact of the COVID-19 pandemic on mental and affective status, perceived well-being, and personal capabilities of outpatients and home care patients with cognitive disorders. METHODS: Prospectively recorded patients in an electronic web registry provided by BlueCompanion Ltd. Up to October 31, 2020, the sample included 90 patients receiving regular care from the Center for Cognitive Disorders and Dementia in Catanzaro Lido, Italy. It was made of 52 ambulatory outpatients and 38 home care patients, mean age 83.3 ± 7.54 years. Participants underwent a multidimensional assessment at baseline (T0) and after 90 days (T1). For each patient, we administered the Mini-Mental State Examination (MMSE) for cognitive functions, the Activities of Daily Living (ADL) and Instrumental ADL (IADL) scales for functional capabilities, the Cumulative Illness Rating Scale (CIRS) for comorbidities and their impact on patients' health, the 5-items Geriatric Depression Scale (GDS) for mood, and the Euro Quality of Life (EuroQoL) for perceived quality of life. Contacts with both ambulatory and home care patients were managed in person or via telephone, preferably through video calls (WhatsApp or FaceTime). RESULTS: Contacts with patients were kept at T0 through telephone. At T1, visits were made in person for over 95% out of the cases. The ADL, IADL, CIRS, GDS, MMSE, and EuroQoL changed slightly between T0 and T1. Most of the patients were clinically stable over time on the majority of the scales explored, but behavioral changes were found in 24.4% of patients and anxiety and insomnia in 17.7% of patients. CONCLUSION: Our study suggests that contacts through telephone and video consultations are likely associated with a health status preservation of the patients.

Prognostic Value of Glycated Hemoglobin in Frail Older Diabetic Patients With Hip Fracture.

Background: Previous studies have shown increased risk of fracture in older patients with poor or strict glycemic control (glycated hemoglobin, HbA1c, ≥ 8% or < 6-7% respectively); however, these reports did not investigate the oldest-old population. Comprehensive geriatric assessment (CGA) and a patient-centered approach have been proven to improve the quality of care in the management of Type 2 Diabetes Mellitus (T2DM) in the older patients, but data regarding T2DM in patients with fragility fractures are still lacking. Aim: To investigate the prognostic role of HbA1c and frailty level in older diabetic patients admitted for hip fracture. Methods: Prospective observational cohort study conducted on diabetic geriatric patients consecutively hospitalized for hip fracture in the orthogeriatric unit of a tertiary care hospital. Preoperative comprehensive geriatric assessment (CGA) was performed. Using the Clinical Frailty Scale (CFS), diabetic patients were categorized in robust (CFS < 5) and frail (CFS ≥ 5), and further stratified according to HbA1c values [Tertile 1 (T1) HbA1c < 48 mmol/mol, Tertile 2 (T2) 48-58 mmol/mol and Tertile 3 (T3) > 58 mmol/mol). Comparisons between continuous variables were performed with analysis of non-parametric test for independent samples, while relationships between categorical variables were assessed by chi-square test. Using logistic multivariate regression, we evaluated the determinants of 1-year all-cause mortality in diabetic older patients with hip fracture. Results: Among the 1319 older patients (mean age 82.8 ± 7.5 years, 75.9% females) hospitalized for hip fracture, 204 (15.5%) had a previous diagnosis of T2DM. T2DM patients showed an increased proportion of multiple concurrent fractures occurred during the accidental fall or syncope (12.7% vs 11.2%, p=0.02). One-year mortality after hip fracture surgery was significantly higher in T2DM as compared to not diabetic patients (21.2% vs 12.5%, p<0.001). No significant difference in mortality was found across HbA1c tertiles; however, frail diabetic patients in the second and third HbA1c tertiles showed higher mortality risk compared to the robust counterparts (26.9% vs 5%, p=0.001 for T2 and 43.5% vs 13.3%, p=<0.05 for T3), while no difference was observed among those in T1. Conclusions: Frail patients with HbA1c ≥ 48 mmol/L showed an increased mortality risk as compared to robust counterparts. CFS represents an important tool to select diabetic subjects with higher likelihood of adverse outcome.

Usefulness of lung ultrasound for selecting asymptomatic older patients with COVID 19 pneumonia.

Clinical and prognostic differences between symptomatic and asymptomatic older patients with COVID-19 are of great interest since frail patients often show atypical presentation of illness. Lung Ultrasound (LUS) has been proven to be a reliable tool for detecting early-phase COVID-19 pneumonic alterations. The current prospective bicentric study aimed to compare LUS score and 3-month overall mortality between asymptomatic and symptomatic older patients with COVID-19, according to frailty status. Patients were stratified according to LUS score tertiles and Clinical Frailty Scale categories. Survival rate was assessed by telephone interviews 3 months after discharge. 64 symptomatic (24 women, aged 80.0 ± 10.8 years) and 46 asymptomatic (31 women, aged 84.3 ± 8.8 years) were consecutively enrolled. LUS score resulted an independent predictor of 3-month mortality [OR 2.27 (CI95% 1.09-4.8), p = 0.03], and the highest mortality rate was observed in symptomatic and asymptomatic pre-frail and frail patients (70.6% and 66.7%, respectively) with greater LUS abnormalities (3rd tertile). In conclusion, LUS identified an acute interstitial lung involvement in most of the older asymptomatic patients. Mortality rate progressively increased according to clinical frailty and LUS score degree, resulting a reliable prognostic tool in both symptomatic and asymptomatic patients.

Astrocyte reactivity with late-onset cognitive impairment assessed in vivo using 11C-BU99008 PET and its relationship with amyloid load.

11C-BU99008 is a novel positron emission tomography (PET) tracer that enables selective imaging of astrocyte reactivity in vivo. To explore astrocyte reactivity associated with Alzheimer's disease, 11 older, cognitively impaired (CI) subjects and 9 age-matched healthy controls (HC) underwent 3T magnetic resonance imaging (MRI), 18F-florbetaben and 11C-BU99008 PET. The 8 amyloid (Aß)-positive CI subjects had higher 11C-BU99008 uptake relative to HC across the whole brain, but particularly in frontal, temporal, medial temporal and occipital lobes. Biological parametric mapping demonstrated a positive voxel-wise neuroanatomical correlation between 11C-BU99008 and 18F-florbetaben. Autoradiography using 3H-BU99008 with post-mortem Alzheimer's brains confirmed through visual assessment that increased 3H-BU99008 binding localised with the astrocyte protein glial fibrillary acid protein and was not displaced by PiB or florbetaben. This proof-of-concept study provides direct evidence that 11C-BU99008 can measure in vivo astrocyte reactivity in people with late-life cognitive impairment and Alzheimer's disease. Our results confirm that increased astrocyte reactivity is found particularly in cortical regions with high Aß load. Future studies now can explore how clinical expression of disease varies with astrocyte reactivity.

Behavioral and Psychological Symptoms in Dementia (BPSD) and the Use of Antipsychotics.

Dementia affects about 47 million people worldwide, number expected to exponentially increase within 30 years. Alzheimer's disease (AD) is the most common dementia type, accounting on its own for almost 70% of all dementia cases. Behavioral and psychological symptoms (BPSD) frequently occur during the disease progression; to treat agitation, aggressiveness, delusions and hallucinations, the use of antipsychotic drugs should be limited, due to their safety issues. In this literature review regarding the use of antipsychotics for treating BPSD in dementia, the advantages and limitation of antipsychotic drugs have been evaluated. The available medications for the management of behavioral and psychological symptoms are the antipsychotics, classed into typical and atypical, depending on their action on dopamine and serotonin receptors. First generation, or typical, antipsychotics exhibit lack of tolerability and display a broad range of side effects such as sedation, anticholinergic effects and extrapyramidal symptoms. Atypical, or second generation, antipsychotics bind more selectively to dopamine receptors and simultaneously block serotonin receptors, resulting in higher tolerability. High attention should be paid to the management of therapy interruption or switch between antipsychotics, to limit the possible rebound effect. Several switching strategies may be adopted, and clinicians should "tailor" therapies, accounting for patients' symptoms, comorbidities, polytherapies and frailty.

Long-term effectiveness and safety of anticoagulation therapy in oldest old, frail people with atrial fibrillation.

BACKGROUND: Atrial Fibrillation (AF) represents a major cause of mortality and morbidity in older people; however, oldest-old frail patients are usually excluded from clinical trials. Aim of the study is to evaluate the impact of oral anticoagulation (OAC) therapy on long-term overall survival and clinically relevant bleedings in a large cohort of hospitalised frail, oldest-old patients with AF. PATIENTS AND METHODS: Prospective, observational, cohort study, evaluating patients consecutively hospitalized for acute illnesses in our Geriatrics Unit (January 2013-July 2017). Participants were divided in two groups, AF and sinus rhythm (SR). Besides recording demographic characteristics and clinical history, comprehensive geriatric assessment (CGA) was obtained. RESULTS: AF patients [1808/5093 (35.5%), 58.5% women] were older, with higher burden of comorbidity than those with SR. At discharge, HAS-BLED [OR 0.77 (95%CI 0.67-0.90), cognitive impairment [OR 0.92 (95%CI 0.90-0.95)], malnutrition [OR 0.74 (95%CI 0.57-0.97)] and CHA2DS2VASc [OR 1.33 (95%CI 1.20-1.47)] emerged as significant independent predictors of anticoagulant prescription. AF patients showed significantly reduced overall survival (OS) than those with SR (11.4 vs 19.4 months, p<.001). However, anticoagulated AF patients (75.2%) had three-times longer OS than those not anticoagulated (15.0 vs 5.6 months, p<.001), comparable to SR patients after adjustment for potential confounders [HR 1.04 (95%CI 0.99-1.10)]. ED readmittance risk for clinically relevant bleeding did not differ between AF patients receiving or not anticoagulation [HR 1.04 (95%CI 0.76-1.14)] CONCLUSION: anticoagulation therapy was associated with significant increase of long-term OS without increased risk of clinically relevant bleeding. CGA resulted an useful tool in OAC therapy decision-making.

Does insulin resistance influence neurodegeneration in non-diabetic Alzheimer's subjects?

BACKGROUND: Type 2 diabetes is a risk factor for Alzheimer's disease (AD), and AD brain shows impaired insulin signalling. The role of peripheral insulin resistance on AD aetiopathogenesis in non-diabetic patients is still debated. Here we evaluated the influence of insulin resistance on brain glucose metabolism, grey matter volume and white matter lesions (WMLs) in non-diabetic AD subjects. METHODS: In total, 130 non-diabetic AD subjects underwent MRI and [18F]FDG PET scans with arterial cannula insertion for radioactivity measurement. T1 Volumetric and FLAIR sequences were acquired on a 3-T MRI scanner. These subjects also had measurement of glucose and insulin levels after a 4-h fast on the same day of the scan. Insulin resistance was calculated by the updated homeostatic model assessment (HOMA2). For [18F]FDG analysis, cerebral glucose metabolic rate (rCMRGlc) parametric images were generated using spectral analysis with arterial plasma input function. RESULTS: In this non-diabetic AD population, HOMA2 was negatively associated with hippocampal rCMRGlc, along with total grey matter volumes. No significant correlation was observed between HOMA2, hippocampal volume and WMLs. CONCLUSIONS: In non-diabetic AD, peripheral insulin resistance is independently associated with reduced hippocampal glucose metabolism and with lower grey matter volume, suggesting that peripheral insulin resistance might influence AD pathology by its action on cerebral glucose metabolism and on neurodegeneration.

Endocrine dysfunction and cognitive impairment.

Dementia is a highly prevalent chronic disease among the older population, affecting more than 50 million people worldwide and representing a huge healthcare, social and economic burden. Dementia, and in particular Alzheimer's disease, prevalence is expected to raise within the next few years. Unfortunately, no disease-modifying therapies are available so far, despite a plethora of clinical trials targeting the hallmarks of Alzheimer's disease. Given these premises, it appears crucial to address not only the neuropathological correlates of the disease, but also the modifiable risk factors. Among them, evidence suggest a role of the endocrine system not only in the brain development, but also in the maintenance of its health, having neurotrophic, antioxidant and metabolic functions crucial for the cognitive abilities. This review focuses on the evidence evaluating the impact of the endocrine systems, in particular thyroid function, insulin resistance, parathyroid hormone, vitamin D and sexual hormones on cognitive status. Results from epidemiological, preclinical and some clinical studies demonstrated the link between thyroid, parathyroid hormone and vitamin D and cognitive status, between diabetes, and insulin resistance in particular, and dementia, between sexual and adrenal hormones, particularly estrogen variation at menopause, and cognitive decline. The growing interest on the modifiable risks factors of cognitive decline increased the knowledge about the complex interplay of endocrine systems and cognition, highlighting the need and the usefulness of a multidisciplinary approach to the prevention of a complex and devastating disease.

Pneumonia Lung Ultrasound Score (PLUS): A New Tool for Detecting Pneumonia in the Oldest Patients.

OBJECTIVES: To compare the diagnostic accuracy of lung ultrasound (LUS) and standard chest X-ray (CXR) in older patients admitted to an acute-care geriatric ward for suspected acute pneumonia, and to develop an easy-to-use diagnostic tool, now called Pneumonia Lung Ultrasound Score (PLUS), for early risk stratification. DESIGN: Prospective, single-center, cohort study. SETTING: Acute-care geriatric ward of tertiary care center. PARTICIPANTS: Individuals, aged 65 years and older, with suspected acute pneumonia. MEASUREMENTS: Participants were stratified according to the Multidimensional Prognostic Index. All the patients underwent CXR and LUS, whereas chest computed tomography was performed in case of mismatch between LUS and CXR. Using logistic multivariate regression, we assessed the influence of age, sex, multimorbidity, cognitive impairment, and clinical biomarkers in the misdiagnosis of acute pneumonia. Finally, an easy-to-perform diagnostic tool based on the combination of biomarkers (brain natriuretic peptide, high-sensitivity C-reactive protein, and partial pressure arterial oxygen/fraction of inspired oxygen ratio) and LUS was realized. A receiver operating characteristic curve was used to verify the predictive accuracy of PLUS, CXR, and LUS in pneumonia diagnosis. RESULTS: A total of 132 subjects (69% women; mean age = 85.3 ± 6.9 years) were enrolled in the study. Acute pneumonia was diagnosed in 94 of 132 cases. LUS showed higher diagnostic accuracy compared with CXR (0.91 (95% confidence interval (CI) = 0.85-0.93) vs 0.67 (95% CI = 0.58-0.75)) in detecting pneumonic consolidations. A higher degree of cognitive impairment was associated with both LUS and CXR pneumonia misdiagnosis (odds ratio = 1.30 (95% CI = 1.04-1.65)). PLUS showed higher predictive accuracy in the diagnosis of acute pneumonia compared with LUS (AUC = 0.92 (95% CI = 0.87-0.98) vs 0.86 (95% CI = 0.80-0.96); P = .029). CONCLUSIONS: This study confirms the higher diagnostic accuracy of LUS compared with CXR for acute pneumonia in older adults. Nonetheless, the accuracy of PLUS, an easy-to-use, biomarker-derived diagnostic tool, was superior to LUS regardless of patients' degree of frailty.