Frailty on the island of Ireland: evidence from the NICOLA and TILDA studies.

BACKGROUND: Aimed to compare the prevalence, characteristics, and associated mortality risk of frailty in Northern Ireland (NI) and the Republic of Ireland (ROI). METHODS: Secondary analysis of the first wave of two nationally representative cohorts, the Northern Ireland Cohort for the Longitudinal Study of Ageing or NICOLA study (N = 8504) and the Irish Longitudinal Study on Ageing or TILDA study (N = 8504). Frailty was assessed using a harmonized accumulation deficits frailty index (FI) containing 30 items. FI scores classified individuals as non-frail (<0.10), pre-frail (0.10-0.24) and frail (≥0.25). Linkage to respective administrative data sources provided mortality information with a follow-up time of 8 years. RESULTS: The prevalence of frailty was considerably higher in NI compared with the ROI (29.0% compared with 15.0%), though pre-frailty was slightly lower (35.8% and 37.3%, respectively). Age, female sex, and lower socio-economic status were consistently associated with a higher likelihood of both pre-frailty and frailty. In the pooled analysis, both frailty and pre-frailty were higher in NI (RR = 2.68, 95% CIs 2.45, 2.94 and RR = 1.30, 95% CIs 1.21, 1.40, respectively). Frailty was associated with an increased mortality risk in both cohorts, even after full adjustment for all other characteristics, being marginally higher in TILDA than in NICOLA (HR = 2.43, 95% CIs 2.03, 2.91 vs. HR = 2.31, 95% CIs 1.90, 2.79). CONCLUSIONS: Frailty is a major public health concern for both jurisdictions. Further research and monitoring are required to elucidate why there is a higher prevalence in NI and to identify factors in early life that may be driving these differences.

The lived experience of frailty: beyond classification and towards a holistic understanding of health.

PURPOSE: Frailty is characterised by decreased physiological reserves and vulnerability to stressors. Although scales, such as the Fried's Frailty Phenotype (FP), Frailty Index (FI), and Clinical Frailty Scale (CFS), are used to identify frailty, the lived experience of frailty remains understudied. METHODS: This cross-sectional observational research involved participants aged 65 years and older from Wave 1 of The Irish Longitudinal Study on Ageing (TILDA). Participants were categorised into four independent groups: three frail groups based on the aforementioned scales and a non-frail group. Quantitative variables, including self-rated health, CASP-19 quality-of-life score, and frequency of social activities, were analysed and described. RESULTS: The study encompassed 1999 participants with an average age of 72 years, of whom 51% were women. FP exclusively identified 1.6% as frail (n = 32), FI 11.7% (n = 233), and CFS 6.8% (n = 135). More than 60% of all those classified as frail reported their health as good, very good, or excellent, with the lowest proportion (64%) being among frail by FI participants. Frail by FI participants exhibited the lowest mean average CASP-19 score, yet it remained relatively high at 39 out of 57 points. Over 77% of all frail individuals engaged in active leisure activities at least once a month. CONCLUSION: This study underscores the need to comprehend frailty holistically beyond its mere identification. It challenges the prevailing belief that frailty inevitably leads to impaired quality of life and limited social engagement. The findings advocate for a reassessment of how both the general public and healthcare professionals perceive frailty.

Cardiovascular disease and the risk of incident falls and mortality among adults aged ≥ 65 years presenting to the emergency department: a cohort study from national registry data in Denmark.

BACKGROUND: Falls cause 58% of injury-related Emergency Department (ED) attendances. Previous research has highlighted the potential role of cardiovascular risk factors for falls. This study investigated the impact of cardiovascular disease (CVD) risk on three-year incident falls, with presentation to the ED, and mortality. METHODS: A matched cohort study design was employed using national registry data from 82,292 adults (33% male) aged ≥ 65 years living in Denmark who attended the ED in 2013. We compared age and gender matched ED attendees presenting with a fall versus another reason. The cohort was followed for three-year incident falls, with presentation to the ED, and mortality. The impact of falls-related CVDs was also examined. RESULTS: Three-year incident falls was twofold higher among age and gender matched ED attendees aged ≥ 65 years presenting with a fall versus another reason at baseline. A presentation of falls with hip fracture had the highest percentage of incident falls in the 65-74 age group (22%) and the highest percentage mortality in all age groups (27-62%). CVD was not a significant factor in presenting with a fall at the ED, nor did it contribute significantly to the prediction of three-year incident falls. CVD was strongly associated with mortality risk among the ED fall group (RR = 1.81, 95% CI: 1.67-1.97) and showed interactions with both age and fall history. CONCLUSION: In this large study of adults aged ≥ 65 years attending the ED utilising data from national administrative registers in Denmark, we confirm that older adults attending the ED with a fall, including those with hip fracture, were at greatest risk for future falls. While CVD did not predict incident falls, it increased the risk of mortality in the three-year follow up with advancing age. This may be informative for the provision of care pathways for older adults attending the ED due to a fall.

Metabolic syndrome accelerates epigenetic ageing in older adults: Findings from The Irish Longitudinal Study on Ageing (TILDA).

Metabolic syndrome (MetS) is a risk factor for the development of diabetes, cardiovascular disease, and all-cause mortality. It has an estimated prevalence of 40 % among older adults. Epigenetic clocks, which measure biological age based on DNA methylation (DNAm) patterns, are a candidate biomarker for ageing. GrimAge is one such clock which is based on levels of DNAm at 100 Cytosine-phosphate-Guanine (CpG) sites. This study hypothesised that those with MetS have 'accelerated ageing' (biological age greater than their chronological age) as indexed by GrimAge. This study examined MetS's association with GrimAge age acceleration (AA) using data from a subsample of 469 participants of the Irish Longitudinal Study on Ageing (TILDA). MetS was defined by National Cholesterol Education Program Third Adult Treatment Panel (ATP III) and International Diabetes Foundation (IDF) criteria, operationalised using the conventional binary cut-off, and as a count variable ranging from 0 to 5, based on the presence of individual components. This study also explored inflammation (as measured by C reactive protein) and metabolic dysfunction (as measured by adiponectin) as possible mediating factors between MetS and GrimAge AA. We found that MetS as defined by IDF criteria was associated with GrimAge AA of 0.63 years. When MetS was treated as a count, each unit increase in MetS score was associated with over 0.3 years GrimAge AA for both ATP III and IDF criteria. Inflammation mediated approximately one third of the association between MetS and GrimAge AA, suggesting that chronic subclinical inflammation observed in MetS has a relationship with DNAm changes consistent with a faster pace of ageing. Metabolic dysfunction mediated the association between MetS and GrimAge AA to a lesser extent (16 %). These data suggest that chronic subclinical inflammation observed in MetS has a relationship with DNAm changes consistent with a greater pace of ageing.

Vitamin D status & associations with inflammation in older adults.

Research studies have observed associations of vitamin D with inflammation but data in representative older adult studies is lacking. We aimed to investigate the association of C-reactive protein (CRP) with vitamin D status in a representative sample of the older Irish population. The concentrations of 25-hydroxyvitamin D (25(OH)D) and CRP was measured in 5,381 community dwelling Irish adults aged ≥50 years from the Irish Longitudinal Study on Ageing (TILDA). Demographic, health and lifestyle variables were assessed by questionnaire and categorical proportions of CRP were generated by vitamin D status and age. Multi-nominal logistic regression was used to investigate the association of 25(OH)D and CRP status. The prevalence (mean; 95% confidence interval (95% CI)) of normal CRP status (0-5 mg/dL) was 83.9% (82.6-85.0%), elevated status (5-10 mg/dL) 11.0% (9.9-12.0%) and high status (>10 mg/dL) was 5.1% (4.5-5.8%). Mean (95% CI) CRP concentrations were lower in those with normal vs. deficient 25(OH)D status (2.02 mg/dL (1.95-2.08) vs. 2.60 mg/dL (2.41-2.82); p<0.0001). In a logistic regression analysis, those with insufficient or sufficient 25(OH)D status were less likely to have a high CRP status compared to those with deficient 25(OH)D status (insufficient: coefficient (CE) -0.732, 95% CI -1.12-0.33, p<0.0001; sufficient: CE -0.599, 95% CI -0.95-0.24, p = 0.001). In conclusion older adults with deficient vitamin D status had higher levels of inflammation as measured by CRP. Given that inflammation is an important pathological driver of chronic diseases of ageing, and that emerging evidence suggests that vitamin D therapy can reduce inflammation in some disease settings, optimising vitamin D status could represent an effective low risk/low-cost pathway to modulate inflammation in community dwelling older adults.

Characterisation of the pro-inflammatory cytokine signature in severe COVID-19.

Clinical outcomes from infection with SARS-CoV-2, the cause of the COVID-19 pandemic, are remarkably variable ranging from asymptomatic infection to severe pneumonia and death. One of the key drivers of this variability is differing trajectories in the immune response to SARS-CoV-2 infection. Many studies have noted markedly elevated cytokine levels in severe COVID-19, although results vary by cohort, cytokine studied and sensitivity of assay used. We assessed the immune response in acute COVID-19 by measuring 20 inflammatory markers in 118 unvaccinated patients with acute COVID-19 (median age: 70, IQR: 58-79 years; 48.3% female) recruited during the first year of the pandemic and 44 SARS-CoV-2 naïve healthy controls. Acute COVID-19 was associated with marked elevations in nearly all pro-inflammatory markers, whilst eleven markers (namely IL-1ß, IL-2, IL-6, IL-10, IL-18, IL-23, IL-33, TNF-α, IP-10, G-CSF and YKL-40) were associated with disease severity. We observed significant correlations between nearly all markers elevated in those infected with SARS-CoV-2 consistent with widespread immune dysregulation. Principal component analysis highlighted a pro-inflammatory cytokine signature (with strongest contributions from IL-1ß, IL-2, IL-6, IL-10, IL-33, G-CSF, TNF-α and IP-10) which was independently associated with severe COVID-19 (aOR: 1.40, 1.11-1.76, p=0.005), invasive mechanical ventilation (aOR: 1.61, 1.19-2.20, p=0.001) and mortality (aOR 1.57, 1.06-2.32, p = 0.02). Our findings demonstrate elevated cytokines and widespread immune dysregulation in severe COVID-19, adding further evidence for the role of a pro-inflammatory cytokine signature in severe and critical COVID-19.

Towards a consensus definition of allostatic load: a multi-cohort, multi-system, multi-biomarker individual participant data (IPD) meta-analysis.

BACKGROUND: Allostatic load (AL) is a multi-system composite index for quantifying physiological dysregulation caused by life course stressors. For over 30 years, an extensive body of research has drawn on the AL framework but has been hampered by the lack of a consistent definition. METHODS: This study analyses data for 67,126 individuals aged 40-111 years participating in 13 different cohort studies and 40 biomarkers across 12 physiological systems: hypothalamic-pituitary-adrenal (HPA) axis, sympathetic-adrenal-medullary (SAM) axis, parasympathetic nervous system functioning, oxidative stress, immunological/inflammatory, cardiovascular, respiratory, lipidemia, anthropometric, glucose metabolism, kidney, and liver. We use individual-participant-data meta-analysis and exploit natural heterogeneity in the number and type of biomarkers that have been used across studies, but a common set of health outcomes (grip strength, walking speed, and self-rated health), to determine the optimal configuration of parameters to define the concept. RESULTS: There was at least one biomarker within 9/12 physiological systems that was reliably and consistently associated in the hypothesised direction with the three health outcomes in the meta-analysis of these cohorts: dehydroepiandrosterone sulfate (DHEAS), low frequency-heart rate variability (LF-HRV), C-reactive protein (CRP), resting heart rate (RHR), peak expiratory flow (PEF), high density lipoprotein cholesterol (HDL-C), waist-to-height ratio (WtHR), HbA1c, and cystatin C. An index based on five biomarkers (CRP, RHR, HDL-C, WtHR and HbA1c) available in every study was found to predict an independent outcome - mortality - as well or better than more elaborate sets of biomarkers. DISCUSSION: This study has identified a brief 5-item measure of AL that arguably represents a universal and efficient set of biomarkers for capturing physiological 'wear and tear' and a further biomarker (PEF) that could usefully be included in future data collection.

Sustaining an ageing population: the role of micronutrients in frailty and cognitive impairment.

Age-related frailty and cognitive decline are complex multidimensional conditions that significantly impact the ability of older adults to sustain functional capacity and independence. While underlying causes remain poorly understood, nutrition continually emerges as one associated risk element. Many studies have addressed the importance of adequate nutrition in delaying the onset of these conditions, but the specific role of micronutrients is not well established. The consideration of pre-frailty as an outcome variable is also limited in the current literature. In this review, we focus on the potential value of maintaining micronutrient sufficiency to sustaining the health of the ageing population. Using data from the Irish longitudinal study on ageing, we consider several vitamins known to have a high prevalence of low status in older adults and their impact on pre-frailty, frailty and cognitive impairment. They include vitamin B12 and folate, both of which are associated with multiple biological mechanisms involved in long-term health, in particular in cognitive function; vitamin D, which has been associated with increased risk of musculoskeletal disorders, depression and other chronic diseases; and the carotenoids, lutein and zeaxanthin, that may help mitigate the risk of frailty and cognitive decline via their antioxidant and anti-inflammatory properties. We show that low concentrations of folate and carotenoids are implicated in poorer cognitive health and that the co-occurrence of multiple nutrient deficiencies confers greatest risk for frailty and pre-frailty in the Irish longitudinal study on ageing cohort. These health associations contribute to evidence needed to optimise micronutrient status for health in the older adult population.

Low vitamin B12 but not folate is associated with incident depressive symptoms in community-dwelling older adults: a 4-year longitudinal study.

This was a longitudinal study utilising the Irish Longitudinal Study on Ageing (n 3849 aged ≥ 50 years) and investigated the relationship between blood plasma folate and B12 levels at baseline (wave 1) and incident depressive symptoms at 2 and 4 years (waves 2 and 3). A score ≥ 9 on the Center for Epidemiological Studies Depression Scale-8 at wave 2 or 3 was indicative of incident depressive symptoms. B12 status profiles (pmol/l) were defined as < 185, deficient low; 185 to < 258, low normal; > 258-601, normal and > 601 high. Folate status profiles (nmol/l) were defined as ≤ 10·0, deficient low; > 10-23·0, low normal; > 23·0-45·0, normal; >45·0, high. Logistic regression models were used to analyse the longitudinal associations. Both B12 and folate plasma concentrations were lower in the group with incident depressive symptoms v. non-depressed (folate: 21·4 v. 25·1 nmol/l; P = 0·0003; B12:315·7 v. 335·9 pmol/l; P = 0·0148). Regression models demonstrated that participants with deficient-low B12 status at baseline had a significantly higher likelihood of incident depression 4 years later (OR 1·51, 95 % CI 1·01, 2·27, P = 0·043). This finding remained robust after controlling for relevant covariates. No associations of folate status with incident depression were observed. Older adults with deficient-low B12 status had a 51 % increased likelihood of developing depressive symptoms over 4 years. The findings highlight the need to further explore the low-cost benefits of optimising vitamin B12 status for depression in older adults.

Association between metabolic syndrome and risk of both prevalent and incident frailty in older adults: Findings from The Irish Longitudinal Study on Ageing (TILDA).

OBJECTIVES: Metabolic syndrome (MetS) is a risk factor for cardiovascular disease, diabetes, and all-cause mortality. Frailty is a condition of decreased multi-system physiological reserve where one has increased vulnerability to stressors. This study aimed to examine if MetS is associated with prevalent and incident frailty over a 4-year follow-up period in an aged population. METHODS: This study used data from waves 1 (2009-2011) and 3 (2014-2015) of The Irish Longitudinal Study on Ageing. Those aged <50 years or without baseline health assessment data were excluded. Baseline MetS status was determined using the National Cholesterol Education Program Third Adult Treatment Panel criteria. Frailty status was identified at both waves, operationalised using Fried's frailty phenotype (FP) and Rockwood's frailty index (FI). Ordinal logistic regression examined the cross-sectional association between MetS and prevalent frailty status. Those with prevalent pre-frailty or frailty were excluded and ordinal logistic regression models examined the association between MetS and incident frailty. Lastly, MetS' longitudinal associations with the five individual components of Fried's FP were examined. Models were adjusted for age, sex, education, smoking, chronic disease history and renal function. RESULTS: Ordinal logistic regression models (n > 5100), showed MetS was associated with prevalent frailty as assessed by both FP (odds ratio (OR) 1.29, p < 0.001) and FI (OR 1.65, p < 0.001). Of those who were non-frail at baseline, 2247 participants had longitudinal FP data, while 3546 participants had longitudinal FI data. Models demonstrated that MetS was associated with an increased likelihood of incident frailty for both FP (OR 1.57, p < 0.001) and FI (OR 1.29, p = 0.014). MetS was found to be associated with incident low physical activity (OR 1.57, p = 0.001) and incident unintentional weight loss (OR 1.59, p = 0.025). CONCLUSIONS: MetS in those ≥50 years was found to be associated with an increased likelihood of incident frailty over a 4-year period, by 57 % when measured by FP and 29 % by FI. MetS should be considered a risk factor for frailty and be taken into considered in any comprehensive geriatric assessment given frailty's dynamic nature and MetS being potentially modifiable.

The bi-directional association between loneliness and depression among older adults from before to during the COVID-19 pandemic.

BACKGROUND: Older adults have both the highest risk of contracting SARS-CoV-2 and in many jurisdictions have had additional restrictions placed on the social interactions. As a result, the COVID-19 pandemic has led to increased depression and loneliness among older adults. Using data from an established cohort of older adults, the aims of this study was to describe changes in loneliness and depression and to examine the directionality of the association between depression and loneliness over a 5-year period that included the early months of the pandemic. METHODS: Data were from The Irish Longitudinal Study on Ageing (TILDA), a large cohort of community-dwelling adults aged 54+. We applied an auto-regressive cross-lagged panel modelling approach to estimate the effect of depression on loneliness and vice versa over three time points. RESULTS: Both depression and loneliness increased significantly in the early months of the pandemic. While the association between loneliness and depression was bi-directional, loneliness was a stronger predictor of depression. CONCLUSION: The strength and bi-directionality of the association between loneliness and depression suggests that interventions to alleviate loneliness may also help reduce depressive symptoms and vice versa.

Differential Associations Between Two Markers of Probable Sarcopenia and Continuous Orthostatic Hemodynamics in The Irish Longitudinal Study on Ageing.

BACKGROUND: Sarcopenia and orthostatic hypotension are growing age-related health burdens associated with adverse outcomes, including falls. Despite a possible pathophysiological link, the association between the 2 disorders is not well elucidated. We sought to investigate this relationship in The Irish Longitudinal Study on Ageing (TILDA). METHODS: Data from 2 858 participants at wave 3 of TILDA were analyzed. Probable sarcopenia was defined as per the European Working Group on Sarcopenia in Older People revised definition cutoffs (hand grip strength [HGS] <27 kg in men, <16 kg in women, and/or 5-chair stand test [5CST] time >15 seconds). Participants underwent an active stand orthostatic test with continuous blood pressure (BP) monitoring. Multilevel mixed-effects models, controlling for possible confounders, were used to assess the effect of probable sarcopenia by HGS and 5CST criteria on the change in BP after standing. RESULTS: HGS- and 5CST-defined probable sarcopenia were independently associated with an attenuated BP recovery at 10-20 seconds poststand (systolic BP: ß -0.54, p < .001; ß -0.25, p < .001). On average, those meeting HGS probable sarcopenia criteria had a significantly lower BP at 20, 30, and 40 seconds (differences in systolic BP: -5.01 mmHg, -3.68 mmHg, -2.32 mmHg, p < .05 for all). Those meeting 5CST probable sarcopenia criteria had a significant difference in systolic BP at 20 seconds (-1.94 mmHg, p = .002) but not at 30 or 40 seconds. CONCLUSION: Probable sarcopenia had a significant association with delayed orthostatic BP recovery, with HGS-defined probable sarcopenia having a stronger association than 5CST-defined probable sarcopenia. Results support a modest but significant pathophysiological link between probable sarcopenia and orthostatic hypotension.

Plasma lutein and zeaxanthin concentrations associated with musculoskeletal health and incident frailty in The Irish Longitudinal Study on Ageing (TILDA).

INTRODUCTION: Lutein and zeaxanthin are diet-derived carotenoids that are proposed to help mitigate frailty risk and age-related declines in musculoskeletal health via their anti-oxidant and anti-inflammatory properties. Therefore, this study aimed to investigate the association between lutein and zeaxanthin status and indices of musculoskeletal health and incident frailty among community-dwelling adults aged ≥50 years in the Irish Longitudinal Study on Ageing (TILDA). METHODS: Cross-sectional analyses (n = 4513) of plasma lutein and zeaxanthin concentrations and grip strength, usual gait speed, timed up-and-go (TUG), probable sarcopenia (defined as grip strength <27 kg in men, <16 kg in women), and bone mass (assessed using calcaneal broadband ultrasound stiffness index) were performed at Wave 1 (2009-2011; baseline). In the longitudinal analyses (n = 1425-3100), changes in usual gait speed (at Wave 3, 2014-2015), grip strength (Wave 4, 2016) and TUG (at Wave 5, 2018), incident probable sarcopenia (at Wave 4) and incident frailty (Fried's phenotype, Frailty Index, FRAIL Scale, Clinical Frailty Scale-classification tree, at Wave 5) were determined. Data were analysed using linear and ordinal logistic regression, adjusted for confounders. RESULTS: Cross-sectionally, plasma lutein and zeaxanthin concentrations were positively associated with usual gait speed (B [95 % CI] per 100-nmol/L higher concentration: Lutein 0.59 [0.18, 1.00], Zeaxanthin 1.46 [0.37, 2.55] cm/s) and inversely associated with TUG time (Lutein -0.07 [-0.11, -0.03], Zeaxanthin -0.14 [-0.25, -0.04] s; all p < 0.01), but not with grip strength or probable sarcopenia (p > 0.05). Plasma lutein concentration was positively associated with bone stiffness index (0.54 [0.15, 0.93], p < 0.01). Longitudinally, among participants who were non-frail at Wave 1, higher plasma lutein and zeaxanthin concentrations were associated lower odds of progressing to a higher frailty category (e.g. prefrailty or frailty) by Wave 5 (ORs 0.57-0.89, p < 0.05) based on the Fried's phenotype, FRAIL Scale and the Clinical Frailty Scale, and in the case of zeaxanthin, Frailty Index. Neither plasma lutein nor zeaxanthin concentrations were associated with changes in musculoskeletal indices or incident probable sarcopenia (p > 0.05). CONCLUSION: Higher plasma lutein and zeaxanthin concentrations at baseline were associated with a reduced likelihood of incident frailty after ~8 years of follow up. Baseline plasma lutein and zeaxanthin concentrations were also positively associated with several indices of musculoskeletal health cross-sectionally but were not predictive of longitudinal changes in these outcomes over 4-8 years.

An examination of the prevalence of metabolic syndrome in older adults in Ireland: Findings from The Irish Longitudinal Study on Ageing (TILDA).

Metabolic syndrome (MetS) consists of the cluster of central obesity, insulin resistance, hypertension and atherogenic dyslipidaemia. It is a risk factor for cardiovascular disease, diabetes, and mortality. The prevalence of MetS has not been described in older adults from a population-representative sample in a European country before. This study aimed to determine the prevalence of MetS in older adults in Ireland and examine the association between MetS and socio-demographic, health, and lifestyle factors. This study used data from a population aged ≥50 years from waves 1 and 3 of the Irish Longitudinal Study on Ageing. The prevalence of MetS using the National Cholesterol Education Program Third Adult Treatment Panel (ATPIII) and the International Diabetes Foundation (IDF) criteria were determined. Weighted logistic regression examined the association between MetS and age, sex, education, and physical activity. MetS status was determined at both waves with transitions examined. 5340 participants had complete data for MetS criteria at wave 1. 33% had MetS according to the ATPIII criteria (32.5%; 95% CI: 31.1, 34.0), with 39% according to the IDF criteria (39.3%; 95% CI: 37.8, 40.8). MetS was more prevalent with advancing age, among males, those with lower educational attainment and lower physical activity. 3609 participants had complete data for both waves- 25% of those with MetS at wave 1 did not have MetS at wave 3 but the overall number of participants with MetS increased by 19.8% (ATPIII) and 14.7% (IDF). MetS is highly prevalent in older adults in Ireland. 40% of the 1.2 million population aged ≥50 years in Ireland meet either the ATPIII or IDF criteria. Increasing age, male sex, lower educational attainment, and lower physical activity were all associated with an increased likelihood of MetS.

Association between vitamin D deficiency and the risk of prevalent type 2 diabetes and incident prediabetes: A prospective cohort study using data from The Irish Longitudinal Study on Ageing (TILDA).

Background: It is hypothesized that vitamin D contributes to the aetiology of type 2 diabetes mellitus (diabetes). This study's objective was to examine the relationships between baseline vitamin D status (as measured by plasma 25-hydroxyvitamin D concentration) and both prevalent diabetes and prospective risk of developing diabetes, including prediabetes, in a population with historically low levels of vitamin D. Methods: In this prospective cohort study, data from The Irish Longitudinal Study on Ageing (TILDA), a nationally representative cohort of adults aged ≥50 years residing in Ireland were analysed, including wave 1 (October 2009-June 2011) (n = 5272) and wave 3 (March 2014-October 2015) (n = 3828). Those aged <50 years at baseline or who did not complete the health assessment were excluded. Logistic regression models examined the associations between baseline vitamin D concentration (nmol/L) with prevalent diabetes status and incident diabetes/prediabetes collected at a 4-year follow-up. Models were adjusted for age, sex, education, body mass index, smoking history, physical activity, use of statins, and the season in which the vitamin D concentration was sampled. Findings: Deficient baseline vitamin D concentration was cross-sectionally associated with an increased likelihood of having prevalent diabetes (Relative Risk Ratio [RRR] 1·5, 95% CI: 1·03, 2·18; p = 0·037). In longitudinal analyses evaluating diabetes status 4 years later, there was a 62% increased likelihood (RRR: 1·62, 95% CI: 1·12, 2·35; p = 0·011) of developing prediabetes for those with vitamin D <30 nmol/L compared to those with ≥75 nmol/L. The rate of progression from prediabetes to diabetes between wave 1 and 3 was observed to be 32·5%. Interpretation: Those with lower concentrations of vitamin D, as measured by 25-hydroxyvitamin D, may have different risk profiles with regards to their glycaemic status. Our study had limited power due to the low incidence of diabetes but showed strong associations with incident prediabetes, so further research is required. Optimising vitamin D status at a population level may significantly reduce diabetes. Funding: TILDA is funded by Atlantic Philanthropies, the Irish Department of Health, and Irish Life, while additional funding was provided by the Irish Department of Agriculture, Food and the Marine (13F492) to cover the cost of 25-hydroxyvitamin D analysis.

Do the frail experience more adverse events from intensive blood pressure control? A 2-year prospective study in the Irish Longitudinal Study on Ageing (TILDA).

BACKGROUND: The 2018 European Society of Cardiology/European Society of Hypertension (ESC/ESH) guidelines for management of hypertension in adults aged ≥65 years recommend a blood pressure (BP) treatment target of 130-139/70-79 mmHg if tolerated. Randomised controlled trials have advocated for lower BP, but this may have adverse outcomes in the frail. Yet, definitions of frailty vary. METHODS: Using a prospective, observational study design, we compared two frailty classifications in their ability to predict short-term adverse outcomes associated with intensive BP control (<130/70 mmHg) in The Irish Longitudinal Study on Ageing (TILDA). Data from participants aged ≥65 treated for hypertension in Wave 1 (W1) between October 2009 and June 2011 were analysed. Frailty was identified by Frailty Phenotype (FP) and the Clinical Frailty Scale (CFS). We formulated 8 participant groups based on frailty-BP combinations. Outcomes at wave 2 (W2) in 2012-2013 were analysed with adjusted binary logistic regression models. FINDINGS: Of 1920 W1 participants aged ≥65 and treated for hypertension, 1229 had full BP/FP and 1282 BP/CFS data. While the FP only identified risk of hospitalisation associated with intensive BP treatment, intensively treated frail-by-CFS participants had no increased or decreased risk of adverse outcomes, but those treated above the target had a higher risk of falls/fractures. In the non-frail by FP, intensive blood pressure treatment was associated with reduced risk of falls/fractures. INTERPRETATION: Different frailty classifications may have different prognostic implications for the purpose of the application of hypertension management guidelines. Our study had limited power due to low frailty prevalences, so further research is needed. Guidelines should specify the recommended frailty identification method/s. In the frail, therapy personalisation is needed.

Biomarker Signatures of Two Phenotypical Prefrailty Types in the Irish Longitudinal Study on Ageing.

We investigated the biomarker signatures of two previously reported phenotypical prefrailty (PF) types in the first wave of The Irish Longitudinal Study on Ageing (TILDA): PF1 (unexplained weight loss and/or exhaustion) and PF2 (one or two among slowness, weakness, and low physical activity). Binary logistic regression models evaluated the independent associations between available plasma biomarkers and each PF type (compared to robust and compared to each other), while adjusting for age, sex, and education. A total of 5307 participants were included (median age 61 years, 53% women) of which 1473 (28%) were prefrail (469 PF1; 1004 PF2), 171 were frail, and 3663 were robust. The PF2 median age was eight years older than the PF1 median age. Higher levels of lutein and zeaxanthin were independently associated with the lower likelihood of PF1 (OR: 0.77, p < 0.001 and OR: 0.81, p < 0.001, respectively). Higher cystatin C was associated with PF1 (OR: 1.23, p = 0.001). CRP (OR: 1.19, p < 0.001), cystatin C (OR: 1.36, p < 0.001), and HbA1c (OR: 1.18, p < 0.001) were independently associated with PF2, while a higher total (OR: 0.89, p = 0.004) and HDL (OR: 0.87, p < 0.001) cholesterol seemed to be PF2-protective. While PF1 seemed to be inversely associated with serum carotenoid concentrations and hence has an oxidative signature, PF2 seemed to have pro-inflammatory, hyperglycemic, and hypolipidemic signatures. Both PF types were associated with higher cystatin C (lower kidney function), but no biomarkers significantly distinguished PF1 vs. PF2. Further research should elucidate whether therapies for different PF types may require targeting of different biological pathways.

Variability and agreement of frailty measures and risk of falls, hospital admissions and mortality in TILDA.

Little is known about the within-person variability of different frailty instruments, their agreement over time, and whether use of repeat assessments could improve the strength of associations with adverse health outcomes. Repeat measurements recorded in 2010-2011 (Wave 1) and 2012 (Wave 2) from The Irish Longitudinal Study on Ageing (TILDA) were used to classify individuals with frailty using the frailty phenotype (FP) and frailty index (FI). Within-person variability and agreement of frailty classifications were assessed using ANOVA and kappa (K) statistics, respectively. Associations of each frailty measure (wave 1, wave 2, or mean of both waves) with risk of falls, hospitalisations and all-cause mortality were assessed using logistic regression. Among 7455 individuals (mean age 64.7 [SD 9.9] years), within-person SD was 0.664 units (95% CI 0.654-0.671) for FP and 2 health deficits (SD 0.050 [0.048-0.051]) for FI. Agreement of frailty was modest for both measures, but higher for FI (K 0.600 [0.584-0.615]) than FP (K 0.370 [0.348-0.401]). The odds ratios (ORs) for all-cause mortality were higher for frailty assessed using the mean of two versus single measurements for FI (ORs for mortality 3.5 [2.6-4.9] vs. 2.7 [1.9-3.4], respectively) and FP (ORs for mortality 6.9 [4.6-10.3] vs. 4.0 [2.8-5.635], respectively). Frailty scores based on single measurements had substantial within-person variability, but the agreement in classification of frailty was higher for FI than FP. Frailty assessed using the mean of two or more measurements recorded at separate visits was more strongly associated with adverse health outcomes than those recorded at a single visit.

Atrial fibrillation and acceleration of frailty: findings from the Irish Longitudinal Study on Ageing.

INTRODUCTION: both atrial fibrillation (AF) and frailty are increasingly prevalent with age. Cross-sectional studies have suggested a relationship between AF and frailty, but longitudinal data are lacking. We explored if the presence of AF was associated with accelerated progression of frailty over 8 years in community-dwelling older adults. METHODS: a longitudinal retrospective case-control study was conducted using data from Waves 1 and 5 of the Irish Longitudinal Study on Ageing (TILDA). Participants with electrocardiographically detected AF at Wave 1 were matched to controls without AF (1:2) based on age and gender. Frailty was assessed using both the frailty phenotype (FP) and a 31-item frailty index (FI). Change in cases' and controls' FP and FI scores from Waves 1 to 5 were modelled using repeated measures analysis of variance (RM-ANOVA). RESULTS: one hundred eighteen TILDA participants with AF at Wave 1 were matched to 236 controls. By FP, participants with AF were not significantly more frail than controls at Wave 1 (P = 0.166) but were at Wave 5 (P = 0.011), and RM-ANOVA suggested that frailty progressed more in participants with AF between Waves 1 and 5 compared with controls (P = 0.033). By FI, participants with AF were significantly more frail at Wave 1 (P < 0.001) and 5 (P = 0.010), and RM-ANOVA did not show a difference in frailty progression between groups (P = 0.955). CONCLUSION: AF may drive the development of the FP. The FP is a pre-disability syndrome and hence may be better than the FI as a focus for disability prevention in adults with AF.

Low folate predicts accelerated cognitive decline: 8-year follow-up of 3140 older adults in Ireland.

OBJECTIVE: To examine associations of plasma folate concentrations and risk of global and domain-specific cognitive decline in older people. METHODS: Data of 3140 participants from The Irish Longitudinal Study on Ageing (TILDA), a nationally-representative cohort of adults aged ≥50 years were used over 8-year follow-up. Biannual cognitive assessments included the Mini-Mental State Examination (MMSE), verbal fluency and immediate and delayed word recall tests (Waves 1-5) and the Montreal Cognitive Assessment, (MoCA) (Waves 1 and 3). Plasma folate concentrations were measured in stored blood collected at baseline. Mixed effects Poisson and linear regression determined associations between baseline folate concentrations and cognition. RESULTS: In multivariable-adjusted models of those aged ≥50 years at baseline, low folate at baseline (<11.2 nmol/L) was associated with higher proportions of MMSE errors (incidence rate ratio [IRR] = 1.10; 95% confidence interval [CI] (1.00, 1.21), lowest vs. highest quintile) over 8 years. Plasma folate <21.8 nmol/L predicted declines in episodic memory for immediate (beta [ß] = -0.26; 95% CI (-0.48, -0.03), ß = -0.29; 95% CI (-0.50, 0.08) and ß = -0.29; (-0.50, -0.08), for lowest three vs. highest quintile) and delayed recall (ß = -0.20; 95% CI (-0.38, -0.01), ß = -0.18; 95% CI (-0.37, -0.01) and ß = -0.19; (-0.36, -0.01) lowest three vs. highest quintile). There were no significant associations in a subsample aged ≥65 years. CONCLUSION: In those aged ≥50 years, lower concentrations of folate may have differential relationships with cognitive domains. Folate <11.2 nmol/L predicted a decline in global cognitive function, while <21.8 nmol/L predicted poorer episodic memory. Low folate was associated with accelerated decline in cognitive function and is an important marker for cognitive decline among older people.