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Ivan Aprahamian,1,2 Marcus K Borges,3 Denise J C Hanssen,2 Hans W Jeuring,2 Richard C Oude Voshaar2 1Group of Investigation on Multimorbidity and Mental Health in Aging (GIMMA), Geriatrics Division, Department of Internal Medicine, Jundiaí Medical School, Jundiaí, Brazil; 2University of Groningen, University Medical Center Groningen, Department of Psychiatry, Groningen, the Netherlands; 3Federal University of Paraná, Department of Psychiatry, Curitiba, BrazilCorrespondence: Ivan Aprahamian, Group of Investigation on Multimorbidity and Mental Health in Aging (GIMMA), Division of Geriatrics, Department of Internal Medicine, Jundiaí Medical School, Jundiaí, Brazil, Email ivan.aprahamian@gmail.comAbstract: Although the public importance of frailty is widely acknowledged by the World Health Organization, physical frailty is still largely neglected in geriatric mental health care. Firstly in this narrative review, we summarize the knowledge on the epidemiology of the association between depression and frailty, whereafter implications for treatment will be discussed. Even though frailty and depression have overlapping diagnostic criteria, epidemiological studies provide evidence for distinct constructs which are bidirectionally associated. Among depressed patients, frailty has predictive validity being associated with increased mortality rates and an exponentially higher fall risk due to antidepressants. Nonetheless, guidelines on the treatment of depression neither consider frailty for risk stratification nor for treatment selection. We argue that frailty assessment enables clinicians to better target the pharmacological and psychological treatment of depression as well as the need for interventions targeting primarily frailty, for instance, lifestyle interventions and reduction of polypharmacy. Applying a frailty informed framework of depression treatment studies included in a meta-analysis reveals that the benefit–harm ratio of antidepressants given to frail depressed patients can be questioned. Nonetheless, frail-depressed patients should not withhold antidepressants as formal studies are not available yet, but potential adverse effects should be closely monitored. Dopaminergic antidepressants might be preferable when slowness is a prominent clinical feature. Psychotherapy is an important alternative for pharmacological treatment, especially psychotherapeutic approaches within the movement of positive psychology, but this approach needs further study. Finally, geriatric rehabilitation, including physical exercise and nutritional advice, should also be considered. In this regard, targeting ageing-related abnormalities underlying frailty that may also be involved in late-life depression such as low-grade inflammation might be a promising target for future studies. The lack of treatment studies precludes firm recommendations, but more awareness for frailty in mental health care will open a plethora of alternative treatment options to be considered.Keywords: frailty, depression, depressive disorder

Marina Maria Biella,1 Marcus Kiiti Borges,1 Jason Strauss,2 Sivan Mauer,3 José Eduardo Martinelli,4 Ivan Aprahamian1,4 1Department and Institute of Psychiatry, Faculty of Medicine, University of São Paulo, São Paulo, Brazil; 2Geriatric Psychiatry, Cambridge Health Alliance, Harvard Medical School, Boston, MA, USA; 3Department of Psychiatry, Tufts Medical Center, Tufts University Scholl of Medicine, Boston, MA, USA; 4Geriatrics & Psychiatry Division, Department of Internal Medicine, Faculty of Medicine of Jundiaí, Jundiaí, BrazilCorrespondence: Ivan AprahamianGroup of Investigation on Multimorbidity and Mental Health in Aging (GIMMA), Internal Medicine Department, Faculty of Medicine of Jundiaí, Jundiaí, BrazilEmail ivan.aprahamian@gmail.comAbstract: This study aims to carry out a narrative review, aiming to update the literature on subsyndromic depression (SD), which is the most prevalent depressive disorder in older adults, and no formal guidelines or consensus are dedicated to this topic. We carried out an electronic search for articles on SD. Relevant articles were retrieved from Pubmed, EMBASE and Web of Science using the search terms “subthreshold depression,” “prevalence,” “treatment” and “older adults” in several combinations. Original articles in English were included from inception to 1st March 2019. No clear consensus exists in the literature on its nosologic classification, diagnostic tools, causes, course, outcomes or management. SD diagnosis should base in depressive symptoms scales and DSM criteria. Treatment relies mainly on collaborative care and psychotherapy. SD is relevant in clinical practice and research in geriatric psychiatry. Given the negative outcomes and potential benefits of treatment, we recommend brief psychotherapy as first-line treatment and use of psychotropic agents in cases with greater severity and/or functional impairment in association with psychotherapy. SD can precede major depressive disorder, but it also may consist of a primary depressive disorder in older adults. Furthermore, adequate treatment of SD can prevent or reduce negative outcomes associated with depressive symptoms such as worsening of clinical comorbidities, loss of functionality, increased demand for health services, and increased mortality.Keywords: subthreshold depression, prevalence, treatment, depressive symptoms, older adults

Introduction: The Clinical-Functional Vulnerability Index (IVCF-20) is a validated multidimensional instrument that has been used in Brazil to evaluate functional disability in frail older adults. The main aim of this study was to assess frailty using this novel screening tool. In addition, to investigate whether frailty was associated with cognitive impairment and functional disability in older adults with affective disorders., Methods: Participants included were over 60 years old, with affective disorders (depressive or anxiety disorders), from two specialized outpatient clinics. The sample was comprised of 46 patients (30% of a total from 153). The following instruments were applied: Clock Drawing Test (CDT), Mini Mental State Examination (MMSE); Verbal Fluency Test (VFT); Pfeffer Questionnaire or Functional Assessment Questionnaire (FAQ); Katz Index; Geriatric Depression Scale (GDS-15); Geriatric Anxiety Inventory (GAI), and IVCF-20 as well as sociodemographic and clinical questionnaires. The association between the variables of interest was estimated using Spearman correlation., Results: This study found a negative correlation between frailty and cognitive decline (MMSE; rs = -0.58; p < 0.001); (VFT; rs = -0.60; p < 0.001); (CDT; rs = -0.47; p = 0.001) and a positive correlation between frailty and depressive symptoms (GDS-15; rs = 0.34; p = 0.019) as well as disability for IADLs (FAQ; rs = 0.69; p < 0.001). However, there was no statistical difference in the association between frailty and anxiety symptoms (GAI; rs = 0.24; p = 0.103) or disability for BADLs (Katz; rs = -0.02; p = 0.895)., Discussion: Our data support that the associations between frailty, cognitive and functional disability are prevalent issues in Psychogeriatrics. Assessing frailty in a multidimensional context is essential using a rapid assessment frailty tool in clinical practice., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Monteiro and Borges.)

Background: Frailty is an important concept for risk stratification in clinical practice, but it is hardly acknowledged at all in mental healthcare settings. This paper aims to assess the impact of frailty on the course of depression and anxiety, and the impact of these affective disorders on the course of frailty., Methods: Lifelines, a prospective population-based cohort study, evaluated 167,729 people living in the northern Netherlands. Frailty was based on the deficit accumulation model, which resulted in a 60-item frailty index (FI) at baseline and a 35-item FI at baseline and 5-year follow-up. Current depressive and anxiety disorders were assessed with the Mini International Neuropsychiatric Interview according to DSM-IV criteria. Bidirectional associations between frailty and affective disorders were investigated using separate multivariable regression analyses in younger (<60 years) and older adults (≥60 years)., Results: The FI was associated with the onset of a depressive disorder (younger adults: odds ratio [OR] = 1.12; 95% confidence interval [CI] 1.11-1.13; older adults: OR = 1.13; 95% CI 1.09-1.16) as well as any anxiety disorder (younger adults: OR = 1.10; 95% CI 1.09-1.10; older adults: OR = 1.07; 95% CI 1.04-1.09). The other way around, depressive disorder and anxiety disorders were associated with an accelerated increase of frailty over time (depressive disorder: younger adults: beta [β] = 0.03, p < 0.001; older adults: β = 0.04, p < 0.001; and any anxiety disorder: younger adults: β = 0.02, p < 0.001; older adults: β = 0.01, p < 0.142), although the effect of anxiety disorders was less equivocal among older adults., Conclusions: Affective disorders are reciprocally related to frailty. Results with respect to the impact of anxiety disorders on frailty suggest most impact at lower levels of frailty. Our results might imply that interventions to slow biological aging should be broadened towards younger and middle-aged people as well as non-frail older patients. To develop targeted treatment, future clinical and epidemiologic studies on the underlying pathways of this bidirectional association are needed., (© 2022 The Authors. Journal of the American Geriatrics Society published by Wiley Periodicals LLC on behalf of The American Geriatrics Society.)

Objective: We aimed to evaluate the prevalence, clinical determinants, and consequences (falls and hospitalization) of frailty in older adults with mental illness., Design: Retrospective clinical cohort study., Setting: We collected the data in a specialized psychogeriatric ward, in Boston, USA, between July 2018 and June 2019., Participants: Two hundred and fourty-four inpatients aged 65 years old and over., Measurements: Psychiatric diagnosis was based on a multi-professional consensus meeting according to DSM-5 criteria. Frailty was assessed according to two common instruments, that is, the FRAIL questionnaire and the deficit accumulation model (aka Frailty Index [FI]). Multiple linear regression analyses were conducted to evaluate the association between frailty and sample demographics (age, female sex, and non-Caucasian ethnicity) and clinical characteristics (dementia, number of clinical diseases, current infection, number of psychotropic, and non-psychotropic medications in use). Multiple regression between frailty assessments and either falls or number of hospital admissions in the last 6 and 12 months, respectively, were analyzed and adjusted for covariates., Results: Prevalence of frailty was high, that is, 83.6% according to the FI and 55.3% according to the FRAIL questionnaire. Age, the number of clinical (somatic) diseases, and the number of non-psychotropic medications were independently associated with frailty identified by the FRAIL. Dementia, current infection, the number of clinical (somatic) diseases, and the number of non-psychotropic medications were independently associated with frailty according to the FI. Falls were significantly associated with both frailty instruments. However, we found only a significant association for the number of hospital admissions with the FI., Conclusion: Frailty is highly prevalent among geriatric psychiatry inpatients. The FRAIL questionnaire and the FI may capture different forms of frailty dimensions, being the former probably more associated with the phenotype model and the latter more associated with multimorbidity.

Objectives: Decision making (DM) is a component of executive functioning, essential for choosing appropriate decisions. Executive dysfunctioning is particularly common in late-life depression, however the literature is scarce on DM. This case-control study aimed to evaluate the DM profile and performance in participants with and without unipolar major depression., Method: The DM profile and performance were assessed by the Melbourne Decision Making Questionnaire and the Iowa Gambling Task (IGT), respectively, in three groups of older adults from a university-based geriatric psychiatry clinic, i.e. current depression ( n  = 30), remitted depression ( n  = 43) and healthy controls ( n  = 59). The Hamilton Depression scale (HAM-D) 21 items, the Hamilton Anxiety scale, and the Mini-Mental State Examination were used to access depressive symptoms, anxiety symptoms, and cognitive impairment, respectively. Multinomial, nominal and binary logistic regression was used to evaluate the associations between depression, depressive symptomatology and DM., Results: In comparison to the control group, patients with current depression presented higher scores in buck-passing and proscratination DM profiles. In the hypervigilance profile, there was a significant difference between current and remitted depression groups. A higher value ​in the HAM-D scale increased the probability of disadvantageous DM profiles. Depressive patients showed a tendency of a higher mean score in both disadvantageous decks (A and B) of IGT. Patients with current depression showed a worse performance compared to the remitted depression group in the IGT netscore., Conclusion: Older adults with current depression showed DM profiles considered maladaptive or disadvantageous compared to both remitted depression and healthy controls groups.

Objectives: Accumulating evidence shows depression as a risk factor for frailty, but studies are mainly population-based and widely differ in their assessment of either depression or frailty. We investigated the association between depression and frailty among geriatric outpatients using different assessment instruments for both conditions., Method: Among 315 geriatric outpatients (mean age 72.1 years, 68.3% female sex) participating the MiMiCS-FRAIL cohort study, major and subthreshold depression were measured with psychiatric diagnostic interview according to DSM-5 criteria (SCID-5) as well as with instruments to screen and measure severity of depressive symptoms (GDS-15 and PHQ-9). Frailty was assessed according to a screening instrument (FRAIL-BR) and a multidimensional Frailty Index (FI-36 items). Multiple logistic and linear regression were performed to assess the association between depression (independent variable) and frailty (dependent variable) adjusted for confounders., Results: Frailty prevalence in patients with no, subthreshold or major depressive disorder increases from either 14.5%, 46.5% to 65.1% when using the FRAIL-BR questionnaire, and from 10.2%, 20.9%, to 30.2% when using the FI-36 index. These association remain nearly the same when adjusted for covariates. Both the FRAIL-BR and the FI-36 were strongly associated with major depressive disorder, subthreshold depression, and depressive symptoms by PHQ-9 and GDS-15., Conclusion: Late life depression and frailty are associated in a dose-dependent manner, irrespective of the used definitions. Nonetheless, to avoid residual confounding, future research on underlying biological mechanisms should preferably be based on formal psychiatric diagnoses and objectively assessment frailty status.

Introduction: Depressive disorder has been conceptualised as a condition of accelerated biological ageing. We operationalised a frailty index (FI) as marker for biological ageing aimed to explore the bidirectional, longitudinal association between frailty and either depressive symptoms or depressive disorder., Methods: A cohort study with 6-year follow-up including 377 older (≥60 years) outpatients with a DSM-IV-defined depressive disorder and 132 never-depressed controls. Site visits at baseline, 2 and 6-year follow-up were conducted and included the CIDI 2.0 to assess depressive disorder and relevant covariates. Depressive symptom severity and mortality were assessed every 6 months by mail and telephone. A 41-item FI was operationalised and validated against the 6-year morality rate by Cox regression (HR FI  = 1.04 [95% CI: 1.02-1.06])., Results: Cox regression showed that a higher FI was associated with a lower chance of remission among depressed patients (HR FI  = 0.98 [95% CI: 0.97-0.99]). Nonetheless, this latter effect disappeared after adjustment for baseline depressive symptom severity. Linear mixed models showed that the FI increased over time in the whole sample (B[SE] = 0.94 (0.12), p < .001) with a differential impact of depressive symptom severity and depressive disorder. Higher baseline depressive symptom severity was associated with an attenuated and depressive disorder with an accelerated increase of the FI over time., Conclusions: The sum score of depression rating scales is likely confounded by frailty. Depressive disorder, according to DSM-IV criteria, is associated with accelerated biological ageing. This argues for the development of multidisciplinary geriatric care models incorporating frailty to improve the overall outcome of late-life depression., (© 2021 The Authors. International Journal of Geriatric Psychiatry published by John Wiley & Sons Ltd.)

Background: To examine the mortality risk of current and life-time depressive as well as anxiety disorders, whether this risk is moderated by sex or age, and whether this risk can be explained by lifestyle and/or somatic health status., Methods: A cohort study (Lifelines) including 141,377 participants (18-93 years) which were followed-up regarding mortality for 8.6 years (range 3.0-13.7). Baseline depressive and anxiety disorders according to Diagnostic and Statistical Manual of Mental Disorders, fourth edition criteria were assessed with the Mini International Neuropsychiatric Interview and lifetime diagnoses by self-report. All-cause mortality was retrieved from Statistics Netherlands. Cox-regression was applied to calculate proportional hazard ratios, adjusted for lifestyle (physical activity, alcohol use, smoking, and body mass index) and somatic health status (multimorbidity and frailty) in different models., Results: The mortality rate of depressive and anxiety disorders was conditional upon age but not on sex. Only in people below 60 years, current depressive and anxiety disorders were associated with mortality. Only depressive disorder and panic disorder independently predicted mortality when all mental disorders were included simultaneously in one overall model (hazard ratio [HR] = 2.18 [95% confidence intervals (CI): 1.56-3.05], p < 0.001 and HR = 2.39 [95% CI: 1.15-4.98], p = 0.020). Life-time depressive and anxiety disorders, however, were independent of each other associated with mortality. Associations hardly changed when adjusted for lifestyle characteristics but decreased substantially when adjusted for somatic health status (in particular physical frailty)., Conclusions: In particular, depressive disorder is associated with excess mortality in people below 60 years, independent of their lifestyle. This effect seems partly explained by multimorbidity and frailty, which suggest that chronic disease management of depression-associated somatic morbidity needs to be (further) improved.

Introduction: Anorexia of aging (AA) is classically associated with depression. However, robust evidence is lacking regarding general clinic populations. Our aim was to evaluate the association between AA and major depressive disorder (MDD) in geriatric outpatients from a middle-income country., Methods: We conducted a cross-sectional analysis of a cohort study. MDD diagnosis was assessed with a psychiatric interview (SCID-5-CV) according to DSM-5 criteria. Depressive symptomatology was assessed by a 15-items Geriatric Depression Scale (GDS) and the PHQ-9 questionnaire. Appetite was measured with the Simple Nutrition Appetite Questionnaire (SNAQ), whereas AA was defined as a SNAQ score ≤13 points). Linear and logistic regression analysis adjusted for potential confounders were applied to assess the association between depressive symptomatology, MDD and AA., Results: Of the total 339 participants, MDD was present in 65. AA was more frequent in patients with MDD compared to non-depressed patients (30.7 versus 7.7%; p<0.001). The SNAQ score was lower in depressed patients (14.5 vs. 16.6, p<0.001). Adjusted for confounding, linear and logistic regression showed a significant association between the GDS score, PHQ-9 score and MDD with the SNAQ score (p<0.001) and cut-off representing AA (p<0.001), respectively. Moreover, MDD and AA interacted significantly with their association with weight loss (p<0.001)., Conclusions: Depression scales (even without somatic complaints) and MDD were associated with AA in geriatric outpatients. AA is associated with weight loss in MDD. Prospective studies should expand these findings., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Objectives: This study aimed to investigate whether frailty could be an explanatory factor of the association between depression and the number of geriatric syndromes., Methods: Cross-sectional baseline data from a cohort study (MiMiCS-FRAIL) were analyzed in a sample of 315 older adults. Depression was measured according to DSM-5 criteria and a self-report questionnaire (PHQ-9). Frailty was assessed according to the FRAIL questionnaire and a 30-item Frailty Index (FI). We considered six geriatric syndromes. Multiple linear regression analyses were performed and adjusted for potential confounders., Results: Multiple linear regression analyses yielded significant associations between depression and geriatric syndromes. These associations decreased substantially in strength when frailty was added to the models. Findings were consistent for different definitions of depression and frailty., Conclusions: Among depressed patients, frailty may be hypothesized as a causal pathway toward adverse health outcomes associated with depression. Longitudinal studies should explore the causality of this association., Clinical Implications: Frailty should be treated or prevented in order to minimize the impact of other geriatric syndromes among depressed older adults. Screening for frailty would be of utmost importance in mental health care, as frailty is neglected especially in this field. Integrated care models are crucial for clinical practice in mental illness care.

Background: The frailty index (FI) is a well-recognized measurement for risk stratification in older people. Among middle-aged and older people, we examined the prospective association between the FI and mortality as well as its course over time in relation to multimorbidity and specific disease clusters., Methods: A frailty index (FI) was constructed based on either 64 (baseline only) or 35 health deficits (baseline and follow-up) among people aged ≥ 40 years who participated in LifeLines, a prospective population-based cohort living in the Northern Netherlands. Among 92,640 participants, multivariable Cox proportional hazard models were fitted to study the hazard ratio (HR) of the FI at baseline, as well as for 10 chronic disease clusters for all-cause mortality over a 10-year follow-up. Among 55,426 participants, linear regression analyses were applied to study the impact of multimorbidity and of specific chronic disease clusters (independent variables) on the change of frailty over a 5-year follow-up, adjusted for demographic and lifestyle characteristics., Results: The FI predicted mortality independent of multimorbidity and specific disease clusters, with the highest impact in people with either endocrine, lung, or heart diseases. Adjusted for demographic and lifestyle characteristics, all chronic disease clusters remained independently associated with an accelerated increase of frailty over time., Conclusions: Frailty may be seen as a final common pathway for premature death due to chronic diseases. Our results suggest that initiating frailty prevention at middle age, when the first chronic diseases emerge, might be relevant from a public health perspective.

Objectives: To evaluate whether fall risk in older adults is associated with the use of selective serotonin receptor inhibitor (SSRI) monotherapy among geriatric outpatients, and whether this association is moderated by the presence of depressive disorder and/or frailty., Methods: Prospective cohort study with a 12-month follow-up and including 811 community-dwelling adults aged 60 or older from a university-based Geriatric Outpatient Unit. Major depressive disorder (MDD) was diagnosed according to DSM-5 criteria; subsyndromal depression as not meeting MDD criteria, but a Geriatric Depression Scale 15-item score ≥ 6 points. Frailty was evaluated with the FRAIL questionnaire. The association between SSRI use, depression, or both as well as the association between SSRI use, frailty, or both with falls were estimated through a generalized estimating equation (GEE) adjusted for relevant confounders., Results: At baseline, 297 patients (36.6%) used a SSRI (82 without remitted depression) and 306 (37.7%) were classified as physically frail. Frailty was more prevalent among SSRI users (44.8% versus 33.7%, p =.004). After 12 months, 179 participants had at least one fall (22.1%). SSRI use, depression as well as frailty were all independently associated with falls during follow-up. Nonetheless, patients with concurrent of SSRI usage and non-remitted depression had no higher risk compared to either remitted SSRI users or depressed patients without SSRIs. In contrast, concurrence of SSRI use and frailty increases the risk of falling substantially above those by SSRI usage or frailty alone., Conclusion: SSRI usage was independently associated with falls. Especially in frail-depressed patients, treatment strategies for depression other than SSRIs should be considered.

Objectives: Significant weight loss and/or loss of appetite is a criterion of a depressive episode. While malnutrition is associated with many adverse health outcomes, the impact of malnutrition in late-life depression has hardly been examined. The present study aims to (1) evaluate the prevalence of malnutrition in depressed older inpatients, and (2) whether and which indices of malnutrition predict adverse health outcomes in late-life depression., Design: A prospective study at 6 months follow-up., Setting: A University-based psychiatric hospital., Participants: 105 older adults (psychiatric inpatients suffering from unipolar MDD)., Measurements: Participants were evaluated according the Mini Nutritional Assessment (MNA) and anthropometric measures to assess their nutritional status. Multiple regression analyses were used to evaluate the association between the MNA score as well as anthropometric measures with either falls or rehospitalization for any reason., Results: Based on the MNA score, 78 (74.3%) patients were at risk of malnutrition and 13 (12.4%) actually presented malnutrition. Malnutrition was associated with a higher age, frailty, lower body mass index, and smaller calf circumference. During follow-up, 21 (20%) patients fell, 27 (25.7%) were rehospitalized, and 3 died (2.9%). The MNA score was associated with adverse health outcomes, but a low calf circumference predicted falling (OR 4.93 [95% CI: 1.42-17.2], p=.012) and a higher calf circumference rehospitalization (OR 1.17 [95% CI: 1.01-1.35], p=.032)., Conclusion: Malnutrition is prevalent in older depressed inpatients. In contrast to subjective proxies for malnutrition, which are common in depression, only objective measures of malnutrition predict adverse health outcomes such as falls and rehospitalization., Competing Interests: No potential conflict of interest was reported by the authors.

Objectives: The aim of the present study was to investigate whether late-life depression (LLD) is associated with incident frailty over time., Design: Prospective cohort study, one-year follow-up., Setting: Geriatric outpatient clinic, Southwestern of Brazil., Participants: 181 follow-up participants aged 60 years or over., Measurements: Depressive disorders were classified as Major Depressive disorder (MDD) or Subthreshold Depression (STD) according to DSM-5 criteria. Depressive symptoms were assessed with validated versions of 15-item Geriatric Depression Scale (GDS-15) and 9-item Patient Health Questionnaire (PHQ-9). We performed binary logistic regressions to estimate the odds ratio (OR) for frailty in LLD adjusting for multiple confounders. Participants who were frail at baseline were excluded from the analyses according to measures of frailty (FRAIL questionnaire and 36-item Frailty Index, FI-36). We also estimated the risk ratio or relative risk (RR) and the risk difference (RD) for incident frailty., Results: We observed a 2 to 4-fold increased risk for incident frailty among participants with LLD. The presence of a depressive disorder was significantly associated with the onset of frailty (adjusted OR for FRAIL and FI-36: 3.07 [95% CI = 1.03 - 9.17] and 3.76 [95% CI = 1.09 - 12.97], respectively. Notably, the risk for frailty due to LLD was significantly higher with the FI-36 compared to the FRAIL (RR: 3.03 versus 2.23). RD was of 17.3% and 12.7% with the FRAIL and the FI-36, respectively., Conclusion: Our data support the association between LLD and incident frailty over one year among geriatric outpatients, reinforcing longitudinal evidence from population-based studies., Competing Interests: No potential conflict of interest was reported by the authors.

Background: To explore the mutual relationship between multimorbidity, mental illness and frailty, we have set-up the Multimorbidity and Mental health Cohort Study in FRAILty and Aging (MiMiCS-FRAIL) cohort. At the population level, multimorbidity, frailty and late-life depression are associated with similar adverse outcomes (i.e. falls, disability, hospitalization, death), share the same risk factors, and partly overlap in their clinical presentation. Moreover, these three variables may share a common underlying pathophysiological mechanism like immune-metabolic dysregulation. The overall objectives of MiMiCS-FRAIL are 1) to explore (determinants of) the cross-sectional and longitudinal relationship between multimorbidity, depression, and frailty among non-demented geriatric outpatients; 2) to evaluate molecular levels of senoinflammation as a broad pathophysiological process underlying these conditions; and 3) to examine adverse outcomes of multimorbidity, frailty and depression and their interconnectedness., Methods: MiMiCS-FRAIL is an ongoing observational cohort study of geriatric outpatients in Brazil, with an extensive baseline assessment and yearly follow-up assessments. Each assessment includes a comprehensive geriatric assessment to identify multimorbidity and geriatric syndromes, a structured psychiatric diagnostic interview and administration of the PHQ-9 to measure depression, and several frailty measures (FRAIL, Physical Phenotype criteria, 36-item Frailty Index). Fasten blood samples are collected at baseline to assess circulating inflammatory and anti-inflammatory cytokines, leukocytes' subpopulations, and to perform immune-metabolic-paired miRome analyses. The primary outcome is death and secondary outcomes are the number of falls, hospital admissions, functional ability, well-being, and dementia. Assuming a 5-year mortality rate between 25 and 40% and a hazard rate varying between 1.6 and 2.3 for the primary determinants require a sample size between 136 and 711 patients to detect a statistically significant effect with a power of 80% (beta = 0.2), an alpha of 5% (0.05), and an R 2 between the predictor (death) and all covariates of 0.20. Local ethical board approved this study., Discussion: Frailty might be hypothesized as a final common pathway by which many clinical conditions like depression and chronic diseases (multimorbidity) culminate in many adverse effects. The MiMiCS-FRAIL cohort will help us to understand the interrelationship between these variables, from a clinical perspective as well as their underlying molecular signature.

Background: In clinical practice it is often challenging to determine whether mood disturbances should be considered a state or trait characteristics. This study is important to understand the influence of temperaments in the diagnosis of depression. The objective of the present study was to compare the frequency of three types of affective temperament (dysthymia, hyperthymia and cyclothymia) among older adults with major depression compared to non-psychiatric control patients., Methods: A case-control study comparing 50 patients with major depression aged 65 years or above with a comparison group of 100 non-psychiatric controls. Affective temperaments were assessed using the TEMPS-A questionnaire. The 17-item Hamilton Depression Rating Scale and the Young mania Rating Scale were used for the assessment of symptoms of depression and mania, respectively., Results: In the sample 80% had an affective temperament, most commonly hyperthymia (67.3%). In depressive patients 48% had criteria for hyperthymic temperament against 77% of the controls (OR= 0.3, 95%CI 0.1-0.7). 38.8% of these patients presented cyclothymic temperament, whereas among controls, 12% fulfilled criteria (OR= 2.9, 95%CI 1.1-7.2)., Limitations: The sample was relatively small, and their educational level was very low., Conclusion: A cyclothymic temperament may predict major depression unlike hyperthymia. Whether the effectiveness of mood stabilizers in unipolar disorder is moderated by a cyclothymic temperament and should be explored in future randomized controlled trials., (Copyright © 2020. Published by Elsevier B.V.)

Objective: Decision-making (DM) is a component of executive functioning. DM is essential to make proper decisions regarding important life and health issues. DM can be impaired in cognitive disorders among older adults, but current literature is scarce. The aim of this study was to evaluate the DM profile in participants with and without cognitive impairment., Design: Cross-sectional analysis of a cohort study on cognitive aging., Participants: 143 older adults., Setting: University-based memory clinic., Methods: Patients comprised three groups after inclusion and exclusion criteria: healthy controls (n=29), mild cognitive impairment (n=81) and dementia (n=33). Participants were evaluated using an extensive neuropsychological protocol. DM profile was evaluated by the Melbourne Decision Making Questionnaire. Multinomial logistic regression was used to evaluate associations between age, sex, educational level, estimated intelligence quotient (IQ), cognitive disorders, depressive or anxiety symptoms, and the DM profiles., Results: The most prevalent DM profile was the vigilant type, having a prevalence of 64.3%. The vigilant profile also predominated in all three groups. The multinomial logistic regression showed that the avoidance profile (i.e. buck-passing) was associated with a greater presence of dementia (p=0.046) and depressive symptoms (p=0.024), but with less anxious symptoms (p=0.047). The procrastination profile was also associated with depressive symptoms (p=0.048). Finally, the hypervigilant profile was associated with a lower pre-morbid IQ (p=0.007)., Conclusion: Older adults with cognitive impairment tended to make more unfavorable choices and have a more dysfunctional DM profile compared to healthy elders.

Background/objectives: Frailty is common in nursing homes. However, few studies reported longitudinal validation for death prediction or cut-off scores with the FRAIL-NH, which is designed to be used in nursing homes. Moreover, no studies came from Latin America, where frailty is highly prevalent. Our objectives were to evaluate (1) the prevalence of frailty according to the FRAIL-NH scale, and (2) its association to and the best cut-off score for predicting death after 12 months., Design: longitudinal study with 12-month follow-up., Setting: 6 nursing homes in southwest of Brazil., Participants: 293 residents with 60 years old or more., Methods: Frailty was evaluated through the FRAIL-NH scale. Logistic regression was used to estimate the associated between frailty and mortality adjusted for age and sex. ROC curve was used to evaluate the accuracy of the scale for mortality prediction., Results: Frailty was prevalent (47.4%) and was associated with death (odds ratio=1.31, 95% confidence interval [CI]=1.18-1.48, p<0.001). The area under the curve was 0.741 (95%CI=0.68-0.79). The sensitivity and specificity of the FRAIL-NH scale according to the best value of the Youden Index was 72.9% and 66.5%, respectively, for a cut-off > 8 points., Conclusions: Frailty is prevalent in nursing homes according to the FRAIL-NH and it was associated with one-year prediction of death for a cut-off > 8 points., Competing Interests: None declared.

Introduction: Cognitive screening instruments are influenced by education and/or culture. In Brazil, as illiteracy and low education rates are high, it is necessary to identify the screening tools with the highest diagnostic accuracy for Alzheimer's disease (AD)., Objective: To identify the cognitive screening instruments applied in the Brazilian population with greater accuracy, to detect AD in individuals with a low educational level or who are illiterate., Methods: Systematic search in SciELO, PubMed and LILACS databases of studies that used cognitive screening tests to detect AD in older Brazilian adults with low or no education., Results: We found 328 articles and nine met the inclusion criteria. The identified instruments showed adequate or high diagnostic accuracy., Conclusion: For valid cognitive screening it is important to consider sociocultural and educational factors in the interpretation of results. The construction of specific instruments for the low educated or illiterate elderly should better reflect the difficulties of the Brazilian elderly in different regions of the country.

Major Depressive Disorder (MDD) can occur in parallel with cognitive impairment. The search for a neuropsychological profile of depression has been pursued in the last two decades. However, scant research has been done on executive functions and decision-making ability (DM)., Objective: To perform a systematic review of the evidence of DM performance evaluated using the Iowa Gambling Task (IGT) in adults with MDD., Methods: A systematic search according to the PRISMA statement was performed on MEDLINE for studies in English using the following keywords: 'depression', 'depressive', 'depressive symptoms' AND 'decision making' OR 'game task'., Results: Five articles that met the inclusion and exclusion criteria were identified. Three reported significant differences between depressed and non-depressed individuals. The results indicated that young adults with MDD exhibited lower performance on all or almost all stages of the IGT. One study that evaluated DM in older adults with MDD showed that depressed non-apathetic participants failed to adopt any advantageous strategy and continued to make risky decisions during the task., Conclusion: Results suggest that performance on the DM task by young and old adults with MDD differed in comparison to non-depressed participants. Given the small number of articles, further studies should be performed., Competing Interests: Disclosure: The authors report no conflicts of interest.

The ANU-ADRI is a self-report tool that assesses risk for Alzheimer's Disease (AD)., Objective: To validate an adapted Portuguese version of this instrument and to carry out the reliability Test-Retest of the ANU-ADRI in Brazil., Methods: In this longitudinal study, the sample was formed (n=100) by two groups (A and B): each comprising 50 patients assisted by GPs (general practitioners) or specialists in dementia. All participants were cognitively healthy upon screening using the MMSE. The ANU-ADRI was applied at baseline (Test) and again within 1 week of the test (Retest)., Results: There was a correlation between the mean scores of the ANU-ADRI Test and Retest (r=0.918, P<0.001). Group A had higher ANU-ADRI scores than those of group B (P<0.05). There was a moderate negative linear relation between the ANU-ADRI and MMSE scores (r= -0.353, P<0.001)., Conclusion: The ANU-ADRI is a valid and reliable instrument to assess whether community-dwelling Brazilians are at greater risk for AD. Low levels of education were associated with higher risk scores on the ANU-ADRI., Competing Interests: Disclosure: The authors report no conflicts of interest.

Alzheimer's disease (AD) represents a major public health problem and it is therefore crucial that modifiable risk factors be known prior to onset of dementia in late-life. The "Australian National University - Alzheimer's Disease Risk Index" (ANU-ADRI) is one of the potential tools for primary prevention of the disease., Objective: The aim of this study was to devise an adapted version of the ANU-ADRI for use in Brazil., Methods: The instrument was translated from its original language of English into Portuguese and then back-translated into English by bilingual translators. It was subsequently reviewed and evaluated as to the degree of translation issues and equivalence. In this study, the ANU-ADRI was applied using individual (face-to-face) interviews in a public hospital, unlike the original version which is applied online by self-report. The final version (pretest) was evaluated in a sample of 10 participants with a mean age of 60 years (±11.46) and mean education of 11 years (±6.32)., Results: The intraclass correlation coefficient (ICC) (inter-rater) was 0.954 (P<0.001 for a confidence interval (CI) of 95%=[0.932; 0.969]). Cultural equivalence was performed without the need for a second instrument application step., Conclusion: After cross-cultural adaptation, the language of the resultant questionnaire was deemed easily understandable by the Brazilian population., Competing Interests: Disclosure: The authors report no conflicts of interest.

Histoplasma capsulatum is a dimorphic fungus that develops a yeast-like morphology in host's tissue, responsible for the pulmonary disease histoplasmosis. The recent increase in the incidence of histoplasmosis in immunocompromised patients highlights the need of understanding immunological controls of fungal infections. Here, we describe our discovery of the role of endogenous galectin-1 (Gal-1) in the immune pathophysiology of experimental histoplasmosis. All infected wild-type (WT) mice survived while only 1/3 of Lgals1 -/- mice genetically deficient in Gal-1 survived 30 days after infection. Although infected Lgals1 -/- mice had increased proinflammatory cytokines, nitric oxide (NO), and elevations in neutrophil pulmonary infiltration, they presented higher fungal load in lungs and spleen. Infected lung and infected macrophages from Lgals1 -/- mice exhibited elevated levels of prostaglandin E 2 (PGE 2 , a prostanoid regulator of macrophage activation) and prostaglandin E synthase 2 ( Ptgs2 ) mRNA. Gal-1 did not bind to cell surface of yeast phase of H. capsulatum , in vitro , suggesting that Gal-1 contributed to phagocytes response to infection rather than directly killing the yeast. The data provides the first demonstration of endogenous Gal-1 in the protective immune response against H. capsulatum associated with NO and PGE 2 as an important lipid mediator in the pathogenesis of histoplasmosis.

Erythropoietin (EPO) is a key hormone involved in red blood cell formation, but its effects on nonerythroid cells, such as macrophages, have not been described. Macrophages are key cells in controlling histoplasmosis, a fungal infection caused by Histoplasma capsulatum (Hc). Considering that little is known about EPO's role during fungal infections and its capacity to activate macrophages, in this study we investigated the impact of EPO pretreatment on the alveolar immune response during Hc infection. The consequence of EPO pretreatment on fungal infection was determined by evaluating animal survival, fungal burden, activation of bronchoalveolar macrophages, inflammatory mediator release, and lung inflammation. Pretreatment with EPO diminished mononuclear cell numbers, increased the recruitment of F4/80(+)/CD80(+) and F4/80(+)/CD86(+) cells to the bronchoalveolar space, induced higher production of IFN-γ, IL-6, MIP-1α, MCP-1, and LTB4, reduced PGE2 concentration, and did not affect fungal burden. As a consequence, we observed an increase in lung inflammation with extensive tissue damage that might account for augmented mouse mortality after infection. Our results demonstrate for the first time that EPO treatment has a deleterious impact on lung immune responses during fungal infection.

It is not known if a physically active lifestyle, without systematic training, is sufficient to combat age-related muscle and strength loss. Therefore, the purpose of this study was to evaluate if the maintenance of a physically active lifestyle prevents muscle impairments due to aging. To address this issue, we evaluated 33 healthy men with similar physical activity levels (IPAQ = 2) across a large range of ages. Functional (torque-angle and torque-velocity relations) and morphological (vastus lateralis muscle architecture) properties of the knee extensor muscles were assessed and compared between three age groups: young adults (30 ± 6 y), middle-aged subjects (50 ± 7 y) and elderly subjects (69 ± 5 y). Isometric peak torques were significantly lower (30% to 36%) in elderly group subjects compared with the young adults. Concentric peak torques were significantly lower in the middle aged (18% to 32%) and elderly group (40% to 53%) compared with the young adults. Vastus lateralis thickness and fascicles lengths were significantly smaller in the elderly group subjects (15.8 ± 3.9 mm; 99.1 ± 25.8 mm) compared with the young adults (19.8 ± 3.6 mm; 152.1 ± 42.0 mm). These findings suggest that a physically active lifestyle, without systematic training, is not sufficient to avoid loss of strength and muscle mass with aging.