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Frailty and delirium are two common geriatric syndromes sharing several clinical characteristics, risk factors, and negative outcomes. Understanding their interdependency is crucial to identify shared mechanisms and implement initiatives to reduce the associated burden. This literature review summarizes scientific evidence on the complex interplay between frailty and delirium; clinical, epidemiological, and pathophysiological commonalities; and current knowledge gaps. We conducted a PubMed systematic search in June 2023, which yielded 118 eligible articles out of 991. The synthesis of the results—carried out by content experts—highlights overlapping risk factors, clinical phenotypes, and outcomes and explores the influence of one syndrome on the onset of the other. Common pathophysiological mechanisms identified include inflammation, neurodegeneration, metabolic insufficiency, and vascular burden. The review suggests that frailty is a risk factor for delirium, with some support for delirium associated with accelerated frailty. The proposed unifying framework supports the integration and measurement of both constructs in research and clinical practice, identifying the geroscience approach as a potential avenue to develop strategies for both conditions. In conclusion, we suggest that frailty and delirium might be alternative—sometimes coexisting—manifestations of accelerated biological aging. Clinically, the concepts addressed in this review can help approach older adults with either frailty or delirium from a different perspective. From a research standpoint, longitudinal studies are needed to explore the hypothesis that specific pathways within the biology of aging may underlie the clinical manifestations of frailty and delirium. Such research will pave the way for future understanding of other geriatric syndromes as well.

Background: Physical frailty and sarcopenia show extensive clinical similarities. Whether biomarkers exist that are shared by the two conditions is presently unclear. Methods: We conducted a systematic review and meta-analysis of cross-sectional and longitudinal studies that investigated the association of frailty and/or sarcopenia with biomarkers as a primary or secondary outcome in adults aged 60 years and older. Only studies published in English that defined frailty using a validated scale and/or questionnaire and diagnosed sarcopenia according to the presence of muscle atrophy plus dynapenia or low physical function were included. Studies were identified from a systematic search of MEDLINE and SCOPUS databases from inception through August 2020. The quality of reporting of each study was assessed by using the Quality Assessment Tool for Observational Cohort, Cross-Sectional and Case-Control studies of the National Institute of Health. A meta-analysis was conducted when at least three studies investigated the same biomarker in both frailty and sarcopenia. Pooled effect size was calculated based on standard mean differences and random-effect models. Sensitivity analysis was performed based on age and the setting where the study was conducted. Results: Eighty studies (58 on frailty and 22 on sarcopenia) met the inclusion criteria and were included in the qualitative analysis. Studies on frailty included 33,160 community-dwellers, hospitalized, or institutionalized older adults (60–88 years) from 21 countries. Studies on sarcopenia involved 4904 community-living and institutionalized older adults (68–87.6 years) from 9 countries. Several metabolic, inflammatory, and hematologic markers were found to be shared between the two conditions. Albumin and hemoglobin were negatively associated with both frailty and sarcopenia. Interleukin 6 was associated with frailty and sarcopenia only in people aged < 75. Community-dwelling older adults with frailty and sarcopenia had

Background: Sleep disturbances are prevalent among older adults and are associated with various individual diseases. The aim of this study was to investigate whether sleep disturbances are associated with the speed of multimorbidity development among older adults. Methods: Data were gathered from the Swedish National study of Aging and Care in Kungsholmen (SNAC-K), an ongoing population-based study of subjects aged 60+ (N = 3363). The study included a subsample (n = 1189) without multimorbidity at baseline (< 2 chronic diseases). Baseline sleep disturbances were derived from the Comprehensive Psychiatric Rating Scale and categorized as none, mild, and moderate–severe. The number of chronic conditions throughout the 9-year follow-up was obtained from clinical examinations. Linear mixed models were used to study the association between sleep disturbances and the speed of chronic disease accumulation, adjusting for sex, age, education, physical activity, smoking, alcohol consumption, depression, pain, and psychotropic drug use. We repeated the analyses including only cardiovascular, neuropsychiatric, or musculoskeletal diseases as the outcome. Results: Moderate–severe sleep disturbances were associated with a higher speed of chronic disease accumulation (ß/year = 0.142, p = 0.008), regardless of potential confounders. Significant positive associations were also found between moderate–severe sleep disturbances and neuropsychiatric (ß/year = 0.041, p = 0.016) and musculoskeletal (ß/year = 0.038, p = 0.025) disease accumulation, but not with cardiovascular diseases. Results remained stable when participants with baseline dementia, cognitive impairment, or depression were excluded. Conclusion: The finding that sleep disturbances are associated with faster chronic disease accumulation points towards the importance of early detection and treatment of sleep disturbances as a possible strategy to reduce chronic multimorbidity among older adults.

Background: Safinamide, as a levodopa adjunct, is effective in reducing motor fluctuations in Parkinson’s disease (PD) patients; however, scarce evidence is available regarding its use in older PD patients. Aim: To evaluate the safety and tolerability of safinamide as an adjunct therapy in patients aged ≥ 60 years with advanced PD. Methods: A retrospective study including 203 PD patients admitted to a geriatric day hospital, who were evaluated following an extensive clinical protocol. Safinamide use was categorized as never used, ongoing, and withdrawn. Potential correlations of Safinamide withdrawal were investigated in stepwise backward logistic regression models. Results: A total of 44 out of 203 participants were current or former users of Safinamide. Overall, 14 (32%) patients discontinued due to treatment-emergent adverse events (TEAEs). Withdrawal was not associated with older age. Conclusions: Safinamide as an adjunct therapy in patients aged ≥ 60 years with advanced PD was found to be safe and well-tolerated in older patients. There were no specific demographic or clinical characteristics associated with suspension.

Background: Little is known about the comparative risk of death with atypical or conventional antipsychotics (APs) among persons with cardiovascular or cerebrovascular disease (CCD). Research design and methods: A cohort study was conducted using five Italian claims databases. New atypical AP users with CCD aged ≥65 (reference) were matched to new conventional AP users. Mortality per 100 person-years (PYs) and hazard ratios (HR), estimated using Cox models, were reported. Incidence and risk of death were estimated for persons having drug–drug interactions. Outcome occurrence was evaluated 180 days after AP initiation. Results: Overall 24,711 and 27,051 elderly new conventional and atypical AP users were identified. The mortality rate was 51.3 and 38.5 deaths per 100 PYs for conventional and atypical AP users. Mortality risk was 1.33 (95%CI: 1.27–1.39) for conventional APs. There was no increased mortality risk with single drug–drug interactions (DDIs) vs. no DDI. AP users with ≥1 DDI had a 29% higher mortality risk compared to no DDI in the first 90 days of treatment (HR: 1.29 (95% CI: 1.00–1.67)). Conclusions: Conventional APs had a higher risk of death than atypical APs among elderly persons with CCD. Having ≥1 DDI was associated with an increased risk of death.

Background: Little is known about the comparative risk of death with atypical or conventional antipsychotics (APs) among persons with cardiovascular or cerebrovascular disease (CCD). Research design and methods: A cohort study was conducted using five Italian claims databases. New atypical AP users with CCD aged ≥65 (reference) were matched to new conventional AP users. Mortality per 100 person-years (PYs) and hazard ratios (HR), estimated using Cox models, were reported. Incidence and risk of death were estimated for persons having drug–drug interactions. Outcome occurrence was evaluated 180 days after AP initiation. Results: Overall 24,711 and 27,051 elderly new conventional and atypical AP users were identified. The mortality rate was 51.3 and 38.5 deaths per 100 PYs for conventional and atypical AP users. Mortality risk was 1.33 (95%CI: 1.27–1.39) for conventional APs. There was no increased mortality risk with single drug–drug interactions (DDIs) vs. no DDI. AP users with ≥1 DDI had a 29% higher mortality risk compared to no DDI in the first 90 days of treatment (HR: 1.29 (95% CI: 1.00–1.67)). Conclusions: Conventional APs had a higher risk of death than atypical APs among elderly persons with CCD. Having ≥1 DDI was associated with an increased risk of death.

The aim of the present study is to investigate the impact of benzodiazepine use on cognitive performance in primary care patients with first cognitive complaints. The association between the exposition to benzodiazepines (short and long half-life) and cognitive performance, evaluated through the Mini Mental State Examination (MMSE), was tested through analysis of the covariance and logistic regression models. Within the 4,249 participants (mean age 77.0 +/- 8.2, 66.4% women), 732 (17%) were on benzodiazepines. When compared with non-users, short- and long-acting benzodiazepine users presented overlapping adjusted MMSE mean scores (respectively, mean MMSE score: 25.3, 95%CI 25.2-25.5; 25.4, 95%CI 25.1-25.7, and 25.9, 95%CI 25.3-26.4; p = 0.156). When tested according to the logistical regression model, after adjusting for potential confounders, no association was found between short and long acting benzodiazepine use and a MMSE < 24 (respectively, OR 0.9, 95%CI 0.7-1.2; OR 0.8, 95%CI 0.7-1.3) as compared with non-users. In conclusion, according to the results of our study, benzodiazepine use seems not to impact on cognitive performance- as assessed with the MMSE- of primary care patients referring to GPs for first cognitive complaints.

Multimorbidity is a common and burdensome condition that may affect quality of life, increase medical needs, and make people live more years of life with disability. Negative outcomes related to multimorbidity occur beyond what we would expect from the summed effect of single conditions, as chronic diseases interact with each other, mutually enhancing their negative effects, and eventually leading to new clinical phenotypes. Moreover, multimorbidity mirrors an accelerated global susceptibility and a loss of resilience, which are both hallmarks of aging. Due to the complexity of its assessment and definition, and the lack of clear evidence steering its management, multimorbidity represents one of the main current challenges for clinicians, researchers, and policymakers. The authors of this article recently reflected on these issues during two twin international symposia at the 2016 European Union Geriatric Medicine Society (EUGMS) meeting in Lisbon, Portugal, and the 2016 Gerontological Society of America (GSA) meeting in New Orleans, USA. The present work summarizes the most relevant aspects related to multimorbidity, with the ultimate goal to identify knowledge gaps and suggest future directions to approach this condition.

Background and purpose: Drugs with anticholinergic properties might have a negative impact on cognition, but findings are still conflicting. The association was evaluated between anticholinergic drugs and cognitive performance in primary care patients with first cognitive complaints. Methods: From April 2013 to March 2014, 353 general practitioners administered the Mini-Mental State Examination (MMSE) to patients presenting with first cognitive complaints. Drug history was collected and the anticholinergic cognitive burden (ACB) was scored and categorized as ACB 0, ACB 1 and ACB 2+. A mixed effect linear regression model was used to assess the association between ACB and MMSE score. Results: Of 4249 subjects entering the study (mean age 77 +/- 8.2 years, 66.4% women and mean years of schooling 8.9 +/- 4.5), 25.8% received at least one drug with anticholinergic action. According to multivariate analysis, and after adjustment for several confounders, subjects with ACB 2+ had a statistically significant lower MMSE score compared with those with ACB 0 (beta -0.63; 95% confidence interval -1.19; -0.07). Subjects with ACB 1 had a non-statistically significant lower MMSE score than those with ACB 0 (beta -0.11; 95% confidence interval -0.37; 0.15). Conclusions: Anticholinergic medication might affect cognitive function in people with first cognitive complaints. Alternatives should be taken into account when possible, balancing the benefits and harms of these medications.

Introduction: Well-conducted observational studies may represent valuable tools for getting insight to disease etiology, detecting the effect of age-related changes, and providing an important perspective on health risk factors and disabilities in an aging population. Nevertheless, this kind of research poses several challenges for researchers. The main aim of this narrative review was to address the potential methodological issues in performing the observational studies in the elderly, the factors that influence their participation, and the possible solutions for overcoming the barriers to research in this population. Methods: Comprehensive search for the papers published in the period from January 1st 1980 until 31st July 2016 in English or Italian was conducted through MEDLINE, Scopus and Web of Science electronic databases. Findings from the included papers were finally summarized. Results: In cohort studies, the following barriers were addressed: sample size calculation, ascertainment of the target population, frequency of data collection, exposure determination, multi factorial loss to follow-up (drop-outs), cognitive impairment, definition of confounders, and ethical aspects. Case-control studies were reported to be prone to the issues like ascertainment of cases and controls, willingness to participate, data accuracy, recall bias, issues related to patients’ multi morbidity, and cognitive impairment. Conclusions: Important factors to consider in research in elderly people include: precise definition of the study population, well conducted recruitment process, engagement with family and home care staff, cognitive impairment assessment and the consequent relevant ethical and legal issues, relief of participant burden in order to minimize withdrawal, and engagement with the media.

Summary: This study analyzed data of bone mineral density (BMD) from a large cohort of adults with Down syndrome (DS). BMD was found to decrease with age more rapidly in these subjects than in the general population, exposing adults with DS to an increased risk of osteoporosis and bone fracture. Introduction: Down syndrome (DS) in adulthood presents with a high prevalence of osteoporosis. However, in DS, bone mineral density (BMD) can be underestimated due to short stature. Furthermore, the rate of age-related decline in BMD and its association with gender in DS has been rarely evaluated or compared with the general population. The present study is aimed at assessing the variation of BMD with age and gender in a sample of adults with DS and to compare these data with those of the general population, after adjusting for anthropometric differences. Methods: Adults with DS, aged 18 or older, were assessed dual-energy-X-ray-absorptiometry (DXA) at the femoral neck and at the lumbar spine. They were compared with the general population enrolled in the National Health and Nutrition Examination Survey (NHANES) 2009–2010 dataset. Bone mineral apparent density (BMAD) was calculated for each individual. Results: DXA was evaluated in 234 subjects with DS (mean age 36.93 ± 11.83 years, ranging from 20 to 69 years; 50.4% females). In the lumbar spine both mean BMD (DS 0.880 ± 0.141 vs. NHANES 1.062 ± 0.167, p < 0.001) and BMAD (DS 0.138 ± 0.020 vs. NHANES 0.152 ± 0.020, p < 0.001) were significantly lower in the DS sample than in the NAHNES cohort. The same trend was observed at the femoral neck in both BMD (DS 0.658 ± 0.128 vs. NHANES 0.835 ± 0.137, p < 0.001) and BMAD (DS 0.151 ± 0.030 vs. NHANES 0.159 ± 0.028, p<0.001). Age was associated with lower femoral neck BMAD in both samples; importantly, this association was significantly stronger in the DS sample. In the lumbar spine region, no significant association between BMAD and age could be observed in both samples. Conclusio

In the literature, different criteria have been validated to identify frail older subjects, which mainly refer to two conceptual models: the cumulative deficit approach proposed by Rockwood and the Physical Frailty (PF) phenotype proposed by Fried. Both models have received empirical validation. Nevertheless, the frailty phenotype is the most widely used and presents a characterized pathophysiologic background. The PF condition depicted by the frailty phenotype has shown to be predictive of major negative health-related outcomes, including mobility disability, disability for activities of daily living, institutionalization, and mortality. At the same time, it cannot be ignored that the PF phenotype presents substantial overlaps with sarcopenia, 'a syndrome characterized by progressive and generalized loss of skeletal muscle mass and strength with a risk of adverse outcomes such as physical disability, poor quality of life and death'. In fact, many of the adverse outcomes of frailty are probably mediated by sarcopenia. Therefore, sarcopenia may be considered both as the biological substrate for the development of PF and the pathway through which the negative health outcomes of frailty ensue. Although PF encompasses only a part of the frailty spectrum, the identification of a definite biological basis (i.e., skeletal muscle decline) opens new venues for the development of interventions to slow or reverse the progression of this condition. Here, we present a novel conceptualisation of PF which will possibly promote significant advancements over the traditional approaches to this syndrome by enabling the precise operationalisation of the condition, a clear identification of the affected population and the rapid translation of findings to the clinical arena.

Purpose: The metabolic syndrome (MetS) is highly prevalent in Western older populations. MetS is an intriguing entity, because it includes potentially reversible risk factors. Some studies have suggested an inverse correlation between MetS and health-related quality of life (HRQoL), but data regarding older subjects are scanty and conflicting. The aim of this study was to assess the association between HRQoL and MetS in older, unselected community-dwelling subjects. Methods: We analyzed data of 356 subjects aged 75+ living in Tuscania (Italy). HRQoL was assessed using the Health Utilities Index, Mark 3. Diagnosis of MetS was defined according to the National Cholesterol Education Program's ATP-III criteria. Results: MetS was reported by 137 (38%) participants. According to linear regression analysis, MetS was associated with significantly better HRQoL in men (B = 0.19 95% CI = 0.06-0.32; p = 0.006), but not in women. Also, when the regression model was analyzed in men, MetS was associated with better HRQoL (B = 0.17, 95% CI = 0.01-0.32; p = 0.035) only among participants aged 80+. No significant associations were found in men between HRQoL and any of the single components of MetS. Conclusions: MetS is not associated with worse HRQoL among community-dwelling elderly; it is associated with significantly better HRQoL among the oldest men. © 2012 Springer-Verlag.