Search

Key Points Question Are alcohol-induced loss of consciousness and heavy weekly alcohol consumption associated with increased risk of future dementia? Findings In this multicohort study of 131 415 adults, a 1.2-fold excess risk of dementia was associated with heavy vs moderate alcohol consumption. Those who reported having lost consciousness due to alcohol consumption, regardless of their overall weekly consumption, had a 2-fold increased risk of dementia compared with people who had not lost consciousness and were moderate drinkers. Meaning The findings of this study suggest that alcohol-induced loss of consciousness is a long-term risk factor for dementia among both heavy and moderate drinkers., Importance Evidence on alcohol consumption as a risk factor for dementia usually relates to overall consumption. The role of alcohol-induced loss of consciousness is uncertain. Objective To examine the risk of future dementia associated with overall alcohol consumption and alcohol-induced loss of consciousness in a population of current drinkers. Design, Setting, and Participants Seven cohort studies from the UK, France, Sweden, and Finland (IPD-Work consortium) including 131 415 participants were examined. At baseline (1986-2012), participants were aged 18 to 77 years, reported alcohol consumption, and were free of diagnosed dementia. Dementia was examined during a mean follow-up of 14.4 years (range, 12.3-30.1). Data analysis was conducted from November 17, 2019, to May 23, 2020. Exposures Self-reported overall consumption and loss of consciousness due to alcohol consumption were assessed at baseline. Two thresholds were used to define heavy overall consumption: greater than 14 units (U) (UK definition) and greater than 21 U (US definition) per week. Main Outcomes and Measures Dementia and alcohol-related disorders to 2016 were ascertained from linked electronic health records. Results Of the 131 415 participants (mean [SD] age, 43.0 [10.4] years; 80 344 [61.1%] women), 1081 individuals (0.8%) developed dementia. After adjustment for potential confounders, the hazard ratio (HR) was 1.16 (95% CI, 0.98-1.37) for consuming greater than 14 vs 1 to 14 U of alcohol per week and 1.22 (95% CI, 1.01-1.48) for greater than 21 vs 1 to 21 U/wk. Of the 96 591 participants with data on loss of consciousness, 10 004 individuals (10.4%) reported having lost consciousness due to alcohol consumption in the past 12 months. The association between loss of consciousness and dementia was observed in men (HR, 2.86; 95% CI, 1.77-4.63) and women (HR, 2.09; 95% CI, 1.34-3.25) during the first 10 years of follow-up (HR, 2.72; 95% CI, 1.78-4.15), after excluding the first 10 years of follow-up (HR, 1.86; 95% CI, 1.16-2.99), and for early-onset (, This cohort study examines the association of overall consumption of alcohol and resultant loss of consciousness with risk for dementia.

Backgroundassessing cardiovascular and mortality risk with conventional biomarkers is challenging in oldest-old due to multimorbidity and polypharmacy. Ceramides are bioactive lipids shown to predict mortality in late middle-aged cohorts.Objectiveto assess whether plasma ceramides have independent prognostic value for mortality among oldest-old (85+).Designlongitudinal cohort study (Helsinki Businessmen Study, HBS) with a 3.5-year follow-up.Setting and subjectssurvivors of HBS (125 men born in 1919–1934) visited the clinic for laboratory and clinical examination.Methodsfunctional status including physical (short physical performance battery) and Montreal Cognitive Assessment (MoCA) cognitive performance was assessed and laboratory examinations included a large set of biomarkers. Plasma ceramide concentration (Cer(d18:1/16:0)) was measured using a targeted liquid chromatography–tandem mass spectrometry assay. Mortality was retrieved from national registers.Resultsmedian age was 88 years, two-thirds had multimorbidity and 59% were on statin treatment. During the follow-up, 22 (18%) men died. In a model adjusted for variables associated with mortality in the whole cohort at P Conclusionsthese data raise the hypothesis that plasma ceramide concentrations and especially Cer(d18:1/1:60) may offer a clinically useful biomarker to evaluate prognosis in very old age. Such biomarkers are needed for geriatrics, where multimorbidity and pharmacotherapies, such as statins are prevalent hampering assessment of prognosis using conventional methods.

Background Biomarkers are needed for frailty, a common phenotype often associated with muscle loss in older people. Plasma gelsolin (pGSN) is a protein largely synthesized and secreted by skeletal muscle. Aims To investigate whether pGSN could be a biomarker of the frailty phenotype and predict mortality. Methods A homogenous cohort of males (born 1919–1934, baseline n = 3490) has been followed since the 1960s. In 2010/11, frailty phenotypes by modified Fried criteria were assessed. pGSN was measured in a convenience subset (n = 469, mean age 83) and re-measured in survivors (n = 127) in 2017. Mortality through December 31, 2018 was retrieved from national registers. Regression models were used for analyses. Results Of 469 males, 152 (32.4%) were robust, 284 (60.6%) prefrail, and 33 (7.0%) frail in 2010/11. There was a graded (p = 0.018) association between pGSN (mean 58.1 ug/mL, SD 9.3) and frailty. After multivariable adjustment, higher pGSN levels were associated with lower odds of having contemporaneous phenotypic prefrailty (OR per 1 SD 0.73, 95% CI 0.58–0.92) and frailty (OR per 1 SD 0.70, 95% CI 0.44–1.11). By 2018, 179 males (38.2%) had died, and higher baseline pGSN predicted a lower 7-year mortality rate (HR per 1 SD 0.85, 95% CI 0.72–1.00). pGSN concentrations in 2010/11 and 2017 were correlated (n = 127, r = 0.34, p Discussion Higher baseline pGSN concentrations were associated with a persistently robust phenotype and lower mortality rate over 7 years in a cohort of octogenarian males with high socioeconomic status and may be a promising laboratory biomarker for the development of a frailty phenotype.

Purpose To examine whether serum cholesterol in early middle age is associated with age-related macular degeneration (AMD) later in life. Methods A group of Helsinki Businessmen Study (HBS) participants (n = 209) were recruited for the study. Total cholesterol (TC), triglyceride and body mass index (BMI) were measured at the HBS baseline visit in 1964-1973. Lipid subfractions, BMI, smoking status and statin use were recorded in 2011 and fundus photographs graded for AMD in 2005-2012. The subjects were genotyped for the main AMD risk single nucleotide polymorphisms (SNPs). Results TC measured at baseline 1964-1973 was significantly higher in subjects later developing intermediate or late AMD (6.67 mmol/l versus 6.20 mmol/l, p = 0.024) or with drusen size of >= 125 mu m (6.68 mmol/l versus 6.21 mmol/l, p = 0.030) compared with the rest of the study population. TC, LDL and TG values at follow-up 2011 were lower in subjects with AMD compared to those without, whereas HDL levels showed no difference. In multivariate analysis, baseline TC associated with intermediate or late AMD (OR 1.59, p = 0.004) and drusen size >= 125 mu m (OR 1.57, p = 0.006) when corrected for age, BMI, AMD risk SNPs and smoking. Lipid values measured 2011 had no associations after correction. Conclusions High systemic total cholesterol in early middle age may have a role in the initial development of AMD, especially in patients later developing large drusen.

Introduction: Individuals in early dementia prevention trials may differ in how much they benefit from interventions depending on their initial risk level. Additionally, modifiable dementia risk scores might be used as surrogate/intermediate outcomes. Methods: In the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER), we investigated in post hoc analyses (N = 1207) whether the cognitive benefits of the 2-year multi-domain lifestyle intervention differed by baseline dementia risk measured with the “LIfestyle for BRAin Health” (LIBRA) score. We also investigated intervention effects on change in LIBRA score over time. Results: Overall, higher baseline LIBRA was related to less cognitive improvement over time. This association did not differ between the intervention and control groups. The intervention was effective in decreasing LIBRA scores over time, regardless of baseline demographics or cognition. Discussion: The cognitive benefit of the FINGER intervention was similar across individuals with different LIBRA scores at baseline. Furthermore, LIBRA may be useful as a surrogate/intermediate endpoint and surveillance tool to monitor intervention success during trial execution.

Background The studies on the association of various midlife risk factors with reaching 90 years or more are scarce. We studied this association in a socioeconomically homogenous cohort of businessmen. Methods The study consists of men (n = 970) from the Helsinki Businessmen Study cohort (born 1919–1928). Five major cardiovascular disease (CVD) risk factors (smoking, BMI, blood pressure, serum lipids, fasting glucose), consumption of alcohol and coffee, self-rated health and self-rated fitness, were assessed in 1974, at an average age of 50 years. The number of major risk factors was tested as a risk burden. The Charlson Comorbidity Index and the RAND-36 (SF-36) Physical and Mental health summary scores were calculated from surveys in year 2000, at age of 73 years. Mortality dates were retrieved through 31 March 2018 from the Population Information System of Finland. Results 244 men survived to the age of 90 representing 25.2% of the study cohort. The survivors had less risk factor burden in midlife, and less morbidity and higher physical health summary score in 2000. Of those with five major risk factors only 7% survived up to 90 years, whereas 51% of those without any risk factors reached that age. Single risk factors reducing odds of reaching 90 years were smoking (odds ratio [OR] 0.48, 95% confidence interval [CI] 0.34–0.67), glucose (0.66, 0.49–0.88), BMI (0.63, 0.46–0.86), and cholesterol (0.71, 0.53–0.96). Conclusion Lack of five major CVD risk factors in midlife strongly increased odds of reaching 90 years of age and also predicted factors related to successful ageing in late life.

Background To examine the effects of the DPP-4i sitagliptin on CV outcomes during and after incident MI in the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS). Methods TECOS randomized 14,671 participants with type 2 diabetes and atherosclerotic cardiovascular disease (ASCVD) to sitagliptin or placebo, in addition to usual care. For those who had a within-trial MI, we analyzed case fatality, and for those with a nonfatal MI, we examined a composite cardiovascular (CV) outcome (CV death or hospitalization for heart failure [hHF]) by treatment group, using Cox proportional hazards models left-censored at the time of the first within-trial MI, without and with adjustment for potential confounders, in intention-to-treat analyses. Results During TECOS, 616 participants had ≥ 1 MI (sitagliptin group 300, placebo group 316, HR 0.95, 95% CI 0.81–1.11, P = 0.49), of which 25 were fatal [11 and 14, respectively]). Of the 591 patients with a nonfatal MI, 87 (15%) died subsequently, with 66 (11%) being CV deaths, and 57 (10%) experiencing hHF. The composite outcome occurred in 58 (20.1%; 13.9 per 100 person-years) sitagliptin group participants and 50 (16.6%; 11.7 per 100 person-years) placebo group participants (HR 1.21, 95% CI 0.83–1.77, P = 0.32, adjusted HR 1.23, 95% CI 0.83–1.82, P = 0.31). On-treatment sensitivity analyses also showed no significant between-group differences in post-MI outcomes. Conclusions In patients with type 2 diabetes and ASCVD experiencing an MI, sitagliptin did not reduce subsequent risk of CV death or hHF, contrary to expectations derived from preclinical animal models. Trial registration clinicaltrials.gov no. NCT00790205

BACKGROUND: Bioimpedance skeletal muscle indices (SMI) are used as a surrogate for skeletal muscle mass, but their associations with physical functioning and obesity need further evaluation. AIMS: To compare the associations of body mass index (BMI), bioimpedance spectroscopy-based calf intracellular resistance (Cri-SMI), and single-frequency bioimpedance analysis (SF-SMI) indices with physical performance and the functioning of community-dwelling older people at risk of or already suffering from sarcopenia. METHODS: Pre-intervention measurements of the screened subjects and the participants of the Porvoo sarcopenia trial (N = 428) were taken. Cri-SMI, whole-body SF-SMI, and BMI were related to hand-grip strength, walking speed, short physical performance battery (SPPB), and the physical component of the RAND-36. RESULTS: Among the older people (aged 75-96), Cri-SMI correlated inversely with age (men r = - 0.113, p

Background: Life expectancy has increased markedly in the past decades. Thus, it is of great importance to understand how people are ageing and if the trajectories of health and disability are changing over time. This study aimed to examine trends in functional abilities and health in independent cohorts of people aged 75–95 over three decades. Methods: This Helsinki Ageing Study consists of repeated cross-sectional postal surveys examining independent cohorts of old people (75, 80, 85 and 90+ years old). This study combined data from four waves (1989, 1999, 2009 and 2019). Results: In the most recent wave, there was an increase in the portion of participants who were able to walk outdoors easily (75-year-olds p=0.03, 80-year-olds p=0.002, 85-year-olds p

Key summary points Aim To review current cardiovascular medications for benefits and potential harms during COVID-19. Findings Several cardiovascular drugs have a potential to protect patients with COVID-19, although evidence is largely based on observational studies and age-specific data are scarce. Message Most current cardiovascular drugs can be safely continued during COVID-19, but general conditions common in older patients must be considered. Supplementary Information The online version contains supplementary material available at 10.1007/s41999-021-00504-5., Purpose In the pathogenesis of severe COVID-19 complications, derangements of renin–angiotensin–aldosterone system (RAAS), vascular endothelial dysfunction leading to inflammation and coagulopathy, and arrhythmias play an important role. Therefore, it is worth considering the use of currently available drugs to protect COVID-19 patients with cardiovascular diseases. Methods We review the current experience of conventional cardiovascular drugs [angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers, anticoagulants, acetosalicylic acid, antiarrhythmic drugs, statins] as well as some other drug classes (antidiabetic drugs, vitamin D and NSAIDs) frequently used by older patients with cardiovascular diseases. Data were sought from clinical databases for COVID-19 and appropriate key words. Conclusions and recommendations are based on a consensus among all authors. Results Several cardiovascular drugs have a potential to protect patients with COVID-19, although evidence is largely based on retrospective, observational studies. Despite propensity score adjustments used in many analyses observational studies are not equivalent to randomised controlled trials (RCTs). Ongoing RCTs include treatment with antithrombotics, pulmonary vasodilators, RAAS-related drugs, and colchicine. RCTs in the acute phase of COVID-19 may not, however, recognise the benefits of long term anti-atherogenic therapies, such as statins. Conclusions Most current cardiovascular drugs can be safely continued during COVID-19. Some drug classes may even be protective. Age-specific data are scarce, though, and conditions which are common in older patients (frailty, comorbidities, polypharmacy) must be individually considered for each drug group. Supplementary Information The online version contains supplementary material available at 10.1007/s41999-021-00504-5.

Background frailty syndrome is common amongst older people. Low physical activity is part of frailty, but long-term prospective studies investigating leisure-time physical activity (LTPA) during the life course as a predictor of frailty are still warranted. The aim of this study is to investigate whether earlier life LTPA predicts frailty in older age. Methods the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) included older adults (aged 60–77 years) from the general population who were at increased risk of cognitive decline. Frailty was assessed for 1,137 participants at a baseline visit using a modified version of Fried’s phenotype, including five criteria: weight loss, exhaustion, weakness, slowness and low physical activity. Self-reported data on earlier life LTPA were available from previous population-based studies (average follow-up time 13.6 years). A binomial logistic regression analysis was used to investigate the association between earlier life LTPA and pre-frailty/frailty in older age. Results the prevalence of frailty and pre-frailty was 0.8% and 27.3%, respectively. In the analyses, pre-frail and frail groups were combined. People who had been physically very active (OR 0.37, 95% CI 0.23–0.60) or moderately active (OR 0.45, 95% CI 0.32–0.65) earlier in life had lower odds of becoming pre-frail/frail than individuals who had been sedentary. Conclusions frailty was rare in this relatively healthy study population, but almost a third of the participants were pre-frail. Earlier life LTPA was associated with lower levels of pre-frailty/frailty. The results highlight the importance of physical activity when aiming to promote healthy old age.

BACKGROUND: Infections have been hypothesised to increase the risk of dementia. Existing studies have included a narrow range of infectious diseases, relied on short follow-up periods, and provided little evidence for whether the increased risk is limited to specific dementia subtypes or attributable to specific microbes rather than infection burden. We aimed to compare the risk of Alzheimer's disease and other dementias across a wide range of hospital-treated bacterial and viral infections in two large cohorts with long follow-up periods. METHODS: In this large, multicohort, observational study, the analysis was based on a primary cohort consisting of pooled individual-level data from three prospective cohort studies in Finland (the Finnish Public Sector study, the Health and Social Support study, and the Still Working study) and an independent replication cohort from the UK Biobank. Community-dwelling adults (≥18 years) with no dementia at study entry were included. Follow-up was until Dec 31, 2012, in the Health and Social Support study, Dec 31, 2016, in the public sector study and the Still Working study, and Feb 7, 2018, in the replication cohort. Through record linkage to national hospital inpatient registers, we ascertained exposure to 925 infectious diseases (using the International Classification of Diseases 10th Revision codes) before dementia onset, and identified incident dementia from hospital records, medication reimbursement entitlements, and death certificates. Hazard ratios (HRs) for the associations of each infectious disease or disease group (index infection) with incident dementia were assessed by use of Cox proportional hazards models. We then repeated the analysis after excluding incident dementia cases that occurred during the first 10 years after initial hospitalisation due to the index infection. FINDINGS: From March 1, 1986, to Jan 1, 2005, 260 490 people were included in the primary cohort, and from Dec 19, 2006, to Oct 1, 2010, 485 708 people were included in the replication cohort. In the primary cohort analysis based on 3 947 046 person-years at risk (median follow-up 15·4 years [IQR 9·8-21·0]), 77 108 participants had at least one hospital-treated infection before dementia onset and 2768 developed dementia. Hospitalisation for any infectious disease was associated with increased dementia risk in the primary cohort (adjusted HR [aHR] 1·48 [95% CI 1·37-1·60]) and replication cohort (2·60 [2·38-2·83]). The association remained when analyses were restricted to new dementia cases that occurred more than 10 years after infection (aHR 1·22 [95% CI 1·09-1·36] in the primary cohort, the replication cohort had insufficient follow-up data for this analysis), and when comorbidities and other dementia risk factors were considered. There was evidence of a dose-response association between the number of episodes of hospital-treated infections and dementia risk in both cohorts (ptrend=0·0007). Although the greatest dementia risk was seen for central nervous system (CNS) infections versus no infection (aHR 3·01 [95% CI 2·07-4·37]), excess risk was also evident for extra-CNS infections (1·47 [1·36-1·59]). Although we found little difference in the infection-dementia association by type of infection, associations were stronger for vascular dementia than for Alzheimer's disease (aHR 2·09 [95% CI 1·59-2·75] versus aHR 1·20 [1·08-1·33] in the primary cohort and aHR 3·28 [2·65-4·04] versus aHR 1·80 [1·53-2·13] in the replication cohort). INTERPRETATION: Severe infections requiring hospital treatment are associated with long-term increased risk of dementia, including vascular dementia and Alzheimer's disease. This association is not limited to CNS infections, suggesting that systemic effects are sufficient to affect the brain. The absence of infection specificity combined with evidence of dose-response relationships between infectious disease burden and dementia risk support the hypothesis that increased dementia risk is driven by general inflammation rather than specific microbes. FUNDING: UK Medical Research Council, US National Institute on Aging, Wellcome Trust, NordForsk, Academy of Finland, and Helsinki Institute of Life Science. CC BY 4.0Correspondence to: Dr Pyry N Sipilä, Clinicum, Department of Public Health, University of Helsinki, Helsinki FI-00014, Finland pyry.sipila@helsinki.fiFunding: UK Medical Research Council, US National Institute on Aging, Wellcome Trust, NordForsk, Academy of Finland, and Helsinki Institute of Life Science.

Over half of outpatient visits are due to physical symptoms; yet, the significance of symptoms in relation to older people's wellbeing and prognosis has gained very little research attention.This study aims to analyze the prognostic value of symptom burden, derived from symptom count and frequency, in an older cohort aged 75 to 95. We also explore the association between symptom burden and psychological wellbeing.Randomly assigned cohorts of community-dwelling people aged 75-95 filled in the postal questionnaire of the Helsinki Aging Study in 2009.Community-based, postal questionnaires (survey response rate 74%).1583 community-dwelling people aged 75-95 in the urban Helsinki area. Main outcomes and measures: The inquired symptoms were dizziness, back pain, joint pain, chest pain or discomfort, shortness of breath, leg pain when walking, loss of appetite, and urinary incontinence. Symptom burden was calculated according to the number of symptoms and their frequency (score range: 0-8). The participants were subdivided into four groups according to their symptom burden. Mortality data was extracted from the Finnish Population Register in 2014. Psychological wellbeing (PWB) was measured using the validated PWB score.Of 1583 participants, 18% reported no symptoms over the past 2 weeks (Group 0), 31% scored 0.5-1 in the symptom burden score (Group 1), 23% scored 1.5-2 (Group 2), and 28% scored 2.5-8 (Group 3). There was a linear relationship between symptom burden and comorbidities, functional status, falls, and PWB. The groups showed a significant difference in 5-year mortality, even adjusted for age, sex, and comorbidities: Group 1 1.18, 95% CI 0.84-1.66; Group 2 1.63, 95% CI 1.15-2.31, and Group 3 2.08, 95% CI 1.49-2.91 compared to Group 0 (p for linearity0.001). Conclusion and relevance: Symptom burden is associated with higher mortality and lower PWB independent of comorbidities in community-dwelling people aged 75-95. We conclude that somatic symptoms need to be assessed when examining the general health status of an aging patient. Self-reported symptoms seem to convey information about health that cannot be derived from medical diagnoses only.

Key summary points Aim To investigate associations of sleep quality and quantity and nutrition in oldest-old men. Findings Sleep quality was associated with nutritional status and vegetable intakes, whereas sleep quantity was linked to fish intake. Message Healthy nutrition may be an important contributor of sleep hygiene in oldest-old men., Introduction Sleep quality and quantity often decline as people age, which may negatively impact health. We examined how nutrition is associated with self-reported sleep quality and quantity in oldest-old community-dwelling men. Methods In this cross-sectional analysis of the Helsinki Businessmen Study (HBS), a random sample of 130 surviving participants underwent a clinical examination in 2017–2018. Food and nutrient intakes were retrieved from 3-day food diaries in 126 men, and sleep quality and quantity were determined with a questionnaire. Nutritional status was assessed using Mini Nutritional Assessment Short Form (MNA-SF), General Health and Vitality were measured with RAND-36/SF-36 health-related quality of life instrument, and albumin and creatinine levels were analyzed from fasting serum samples. Results Mean age of the survivors was 87 years (range 83–99). Self-reported sleep quality and quantity were highly correlated (p

Background Dementia is a condition which results in a high cost of care, a significant proportion of which is the cost associated with informal care. In previous studies, informal caregiving has been challenging to assess due to difficulties in estimating the true time spent on caregiving work and how to value caregivers’ time. The aim of this study was to compare the costs of dementia among patients living alone and among those living with a caregiver to show the monetary value of informal caregiving from a societal perspective. Methods Data from our four dementia trials using the same measures were combined, allowing the inclusion of 604 participants. Participants were followed up for 2 years or until death for their use of health and social services. Use of all services was retrieved from medical/social records. We also included the costs of lost productivity of those caregivers who were not retired. Results The total mean cost of services and lost productivity was €22,068/person-year (pyrs). Participants living alone had a mean cost of €45,156/pyrs, whereas those living with a spouse had a mean cost of €16,416/pyrs (mean cost ratio 2.99, 95% confidence interval 2.64–3.39). Participants living alone and having Conclusions Detailed data of service use and characteristics of people with dementia showed that from a societal perspective, living alone is a very strong determinant of service use in dementia. Informal caregivers do invaluable work for society.

SummaryBackgroundInfectious diseases have been hypothesised to increase the risk of dementia. However, the evidence is sparse, captures only a limited range of infectious diseases, and relies on short follow-up periods. We assessed a wide range of severe (hospital-treated) bacterial and viral infections and their subtypes as risk factors for dementia in three large cohorts followed up for almost two decades and replicated the main findings in the UK Biobank.MethodsFor primary analysis, we pooled individual-level data from three prospective cohort studies with a median follow up of 19 years (from 1986-2005 to 2012-2016) and a total of 273 125 dementia-free community-dwelling participants. The replication analysis with the UK Biobank was based on 492 146 individuals (median follow-up 9·0 years from 2006-2010 to 2018). We ascertained exposure to infectious diseases and their subtypes before dementia onset using linked records from national hospital inpatient registers. Incident dementia was identified from linked hospital inpatient and outpatient records, medication reimbursement entitlements, and death certificates.FindingsIn the primary analysis based on 5·3 million person-years at risk, 88 099 participants had a hospital-treated infection before dementia onset and 3064 developed dementia. Gram-negative bacterial infections (hazard ratio [HR] 1·64; 95% confidence interval [CI] 1·25–2·14) and herpesvirus infections (HR 1·96; 95% CI 1·31–2·93) were robustly associated with an increased risk of dementia. For these infections, the relative risk of dementia remained similar when reverse causation and ascertainment biases were minimised by assessing only new dementia cases that occurred more than 10 years after the infection, and when comorbidities and potential confounders were considered. The associations were replicated in the UK Biobank with stronger relations observed for vascular dementia than Alzheimer’s disease. In contrast to gram-negative bacterial and herpesvirus infections, the hazard ratio for all bacterial infections combined attenuated from 1·60 (95% CI 1·48–1·72) to 1·27 (95% CI 1·14–1·41) when bias was minimised. For all viral infections, the corresponding attenuation was from HR 1·63 (95% CI 1·32–2·00) to 1·19 (95% CI 0·87–1·62).InterpretationGram-negative bacterial infections and herpesvirus infections were associated with a moderately increased risk of dementia both in the short- and long-term. Hospital-treated bacterial and viral infections in general had only modest long-term associations with incident dementia.FundingUK Medical Research Council, US National Institute on Aging, NordForsk, Academy of Finland, Helsinki Institute of Life Science.Research in contextEvidence before this studyInfectious diseases have been hypothesised in the aetiology of dementia. We searched PubMed on 2 April 2020 for observational studies and systematic reviews using the search terms ((Alzheimer* OR dementia) AND infectio* AND ((systematic[sb]) OR (Observational Study[ptyp])) without restrictions on language or publication date. We also searched the reference lists and citations of relevant articles. In observational studies, infectious diseases in general and specific bacterial (sepsis, septicaemia, bacteraemia, pneumonia, osteomyelitis, urinary tract infection, cellulitis, syphilis, and Borrelia burgdorferi and Chlamydia pneumoniae infections) and viral infections (hepatitis C infection, HIV) are linked to an increased risk of dementia. Additionally, there was suggestive evidence for associations of herpesvirus infections, Toxoplasma gondii parasite infection, and poor oral health with dementia. However, no large-scale studies assessed a wide range of different types of infectious diseases systematically in a single analytical setting and with adequate control for potential sources of bias, such as reverse causation resulting from the systemic changes related to the preclinical stages of dementia that increase susceptibility to infectious diseases.Added value of this studyIn this multicohort study, the primary analysis was based on individual-level data from 273 125 dementia-free community-dwelling participants with a median follow-up of 19 years. We ascertained 528 different infectious diseases before dementia onset using national hospital inpatient records and categorised them by causative microorganism (bacteria, viruses), disease invasiveness (invasive vs localised bacterial infections), and subtype (extracellular vs intracellular lifestyle and cell wall structure of bacteria, and type of virus). When reverse causation was minimised by analysing only infections that occurred more than 10 years before dementia onset, the relative risk of dementia was modest for all bacterial infections combined (hazard ratio [HR] 1·27; 95% confidence interval [CI] 1·14–1·41) and for all viral infections combined (HR 1·19; 95% CI 0·87–1·62). The associations of bacterial infections with dementia did not differ by the invasiveness of the infection (invasive vs localised infections) or extracellular vs intracellular lifestyle of the causative microorganism. In analysis of specific diagnostic groups, robust and stronger long-term associations with dementia were observed for Gram-negative bacterial infections (HR 1·64, 95% CI 1·25–2·14 for full follow-up; HR 1·67, 95% CI 1·13–2·48 from year 10 onwards) and herpesvirus infections (HR 1·96, 95% CI 1.31–2.93 full follow-up; HR 1·92, 95% CI 1·11–3·32 from year 10 onwards). These associations remained after controlling for comorbidities and potential confounders and were replicated in an independent cohort of 492 146 individuals from the UK Biobank (median follow-up 9·0 years) with stronger relations observed for vascular dementia than Alzheimer’s disease.Implications of all the available evidenceGram-negative bacterial infections and herpesvirus infections seem to be robust long-term risk factors for dementia. Further mechanistic and molecular research is warranted to clarify the potential role of Gram-negative bacterial infections and herpesvirus in neurodegeneration and the aetiology of dementia.

ObjectivesTo study the association between retirement characteristics and frailty in a homogenous population of former business executives.DesignCross-sectional cohort study using data from the Helsinki Businessmen Study.SettingHelsinki, Finland.Participants1324 Caucasian men, born in 1919–1934, who had worked as business executives and managers and of whom 95.9% had retired by the year 2000. Questions on age at and type of retirement, lifestyle and chronic conditions were embedded in questionnaires.Primary and secondary outcome measuresFrailty assessed according to a modified phenotype definition at mean age 73.3 years.ResultsMean age at retirement was 61.3 years (SD 4.3) and 37.1% had retired due to old age. The prevalence of frailty was lowest among men retiring at ages 66–67 years but increased among those who worked up to age 70 years or older. Compared with men who retired before age 55 years, those retiring at ages 58–69 years were at decreased risk of frailty in old age relative to non-frailty (adjusted ORs 0.07–0.29, pConclusionExiting working life early and continuing to be occupationally active until age 70 years and older were both associated with increased risk of frailty among the men. Promotion of longer work careers could, however, promote healthier ageing, as the lowest prevalence of frailty was observed in former business executives who retired at ages 66–67 years.

Maxime Billot,1,2 Riccardo Calvani,3,4 Annele Urtamo,5 Juan Luis Sánchez-Sánchez,6 Cecilia Ciccolari-Micaldi,1 Milan Chang,7,8 Regina Roller-Wirnsberger,9 Gerhard Wirnsberger,10 Alan Sinclair,11 Nieves Vaquero-Pinto,12 Satu Jyväkorpi,5 Hanna Öhman,5 Timo Strandberg,13,14 Jos MGA Schols,15 Annemie MWJ Schols,16 Nick Smeets,17 Eva Topinkova,18 Helena Michalkova,19 Anna Rita Bonfigli,20 Fabrizia Lattanzio,20 Leocadio Rodríguez-Mañas,21 Hélio Coelho-Júnior,4 Marianna Broccatelli,4 Maria Elena D’Elia,4 Damiano Biscotti,4 Emanuele Marzetti,3,4 Ellen Freiberger22 1Clinical Gerontology, University Hospital of Limoges, Limoges, France; 2PRISMATICS (Predictive Research in Spine/Neurostimulation Management and Thoracic Innovation in Cardiac Surgery), Poitiers University Hospital, Poitiers, France; 3Università Cattolica del Sacro Cuore, Rome, Italy; 4Fondazione Policlinico Universitario "Agostino Gemelli" IRCCS, Rome, Italy; 5University of Helsinki, Department of General Practice and Primary Health Care, Helsinki University Central Hospital, Unit of Primary Health Care, Helsinki, Finland; 6Foundation for Biomedical Research Getafe University Hospital, Madrid, Spain; 7Faculty of Health Promotion, Sports and Leisure Studies, School of Education, University of Iceland, Reykjavik, Iceland; 8The Icelandic Gerontological Research Center, Landspitali University Hospital and University of Iceland, Reykjavik, Iceland; 9Medical University of Graz, Department of Internal Medicine, Graz, Austria; 10Medical University of Graz, Division of Nephrology, Department of Internal Medicine, Graz, Austria; 11Foundation for Diabetes Research in Older People, Diabetes Frail Ltd., Luton, UK; 12University Hospital of Ramon Cajal IRYCIS, Madrid, Spain; 13University of Helsinki, Clinicum, Helsinki, Finland; Helsinki University Hospital, Medicine and Rehabilitation, Helsinki, Finland; 14University of Oulu, Center for Life Course Health Research, Oulu, Finland; 15Department of Health Services Research, Maastricht University Medical Center, Maastricht, The Netherlands; 16Department of Respiratory Medicine, School of Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University Medical Center, Maastricht, The Netherlands; 17Department of Health & Fitness, Maastricht University Medical Center, Maastricht, The Netherlands; 18 First Faculty of Medicine, Charles University, Prague, Czech Republic; 19Faculty of Social and Health Sciences, South Bohemian University, Ceske Budejovice, Czech Republic; 20Scientific Direction, IRCCS INRCA, Ancona, Italy; 21Geriatrics Service, University Hospital of Getafe, Madrid, Spain; 22Institute for Biomedicine of Aging, FAU Erlangen-Nürnberg, Nürnberg, GermanyCorrespondence: Maxime Billot CHU De Poitiers, PRISMATICS (Predictive Research in Spine/Neurostimulation Management and Thoracic Innovation in Cardiac Surgery)Poitiers University Hospital, 2 Rue De La Miléterie, Poitiers 86021, FranceTel +33 549 443 224Email maxime.billot2@gmail.comAbstract: One of the most widely conserved hallmarks of aging is a decline in functional capabilities. Mobility loss is particularly burdensome due to its association with negative health outcomes, loss of independence and disability, and the heavy impact on quality of life. Recently, a new condition, physical frailty and sarcopenia, has been proposed to define a critical stage in the disabling cascade. Physical frailty and sarcopenia are characterized by weakness, slowness, and reduced muscle mass, yet with preserved ability to move independently. One of the strategies that have shown some benefits in combatting mobility loss and its consequences for older adults is physical activity. Here, we describe the opportunities and challenges for the development of physical activity interventions in people with physical frailty and sarcopenia. The aim of this article is to review age-related physio(patho)logical changes that impact mobility in old age and to provide recommendations and procedures in accordance with the available literature.Keywords: physical exercise, muscle mass, strength, walking, balance, better aging

The hexanucleotide repeat expansion in intron 1 of the C9orf72 gene causes amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. In addition to the effects of the pathogenic expansion, a role of intermediate-length alleles has been suggested in ALS, corticobasal degeneration and Parkinson’s disease. Due to the rarity of intermediate-length alleles with over 20 repeats and the geographical variability in their frequency, large studies that account for population stratification are needed to elucidate their effects. To this aim, we used repeat-primed PCR and confirmatory PCR assays to determine the C9orf72 repeat allele lengths in 705 ALS patients and 3958 controls from Finland. After exclusion of expansion carriers (25.5% of the ALS patients and 0.2% of the controls), we compared the frequency of intermediate-length allele carriers of 525 ALS cases and 3950 controls using several intermediate-length allele thresholds (7–45, 17–45, 21–45, 24–45 and 24–30). The carriership of an intermediate-length allele did not associate with ALS (Fisher’s test, all p ≥ 0.15) nor was there any association with survival (p ≥ 0.33), when we divided our control group into three age groups (18–65, 66–84 and 85–105 years). Carriership of two intermediate-length alleles was associated with ALS, when the longer allele was ≥ 17 repeats (p = 0.002, OR 5.32 95% CI 2.02–14.05) or ≥ 21 repeats (p = 0.00016, OR 15.21 95% CI 3.79–61.0). Our results show that intermediate-length alleles are a risk factor of ALS when present in both alleles, whereas carrying just one intermediate-length allele was not associated with ALS or survival.

Background: Sirtuin-6 (SIRT6) is involved in various crucial cellular pathways, being a key regulator of telomere structure, DNA repair, metabolism, transcriptional control and the NF-kappa B pathway. Sirt6 knock-out mice have been reported to develop typical features of aging and senescence at the age of 2-3 weeks and die within 4 weeks. The aim of this study was to investigate whether sequence variations of SIRT6 are associated with aging and longevity in Finnish men. Methods: The sample of this study consisted of 43 longer-living and healthy males and 92 male control subjects who have died of natural causes at an average age of 66,6 (+/- 4,1) years and who belonged to the Helsinki Birth Cohort Study (HBCS). Single nucleotide polymorphisms (SNPs) in the exons and their surroundings of the SIRT6 were studied using direct PCR sequencing. Results: The SNP rs117385980 (C > T), situated 23 bases downstream of the exon 2 exon/intron border was found in heterozygous form in 1/43 longer-living healthy men (Minor allele frequency (MAF) 0,0116) and in 9/92 controls (MAF 0,0489). To replicate this finding, we studied a group of 63 healthy men at an average age of 83 years from the Helsinki Businessmen Study (HBS)-cohort. The heterozygosity of the same SNP was seen in 2/63 men from the HBS-cohort (MAF 0,0159). Fisher exact test was performed in our two combined study samples. The P-value for all samples combined was 0.07 and the odds ratio 3.53 (95% confidence interval 0.96-13.4). Conclusions: These results suggest an inverse association between the T allele of rs117385980 and longevity. The result needs to be confirmed in a larger study. It remains to be determined whether rs117385980 itself has an effect or if it is a mere genetic marker for some other yet undiscovered sequence variant causing a functional effect.

Correction: Volume: 292 Pages: 160-162 DOI: 10.1016/j.atherosclerosis.2019.11.020 Published: JAN 2020

ObjectiveThe task force of the International Conference of Frailty and Sarcopenia Research (ICFSR) developed these clinical practice guidelines to overview the current evidence-base and to provide recommendations for the identification and management of frailty in older adults.MethodsThese recommendations were formed using the GRADE approach, which ranked the strength and certainty (quality) of the supporting evidence behind each recommendation. Where the evidence-base was limited or of low quality, Consensus Based Recommendations (CBRs) were formulated. The recommendations focus on the clinical and practical aspects of care for older people with frailty, and promote person-centred care.Recommendations for Screening and AssessmentThe task force recommends that health practitioners case identify/screen all older adults for frailty using a validated instrument suitable for the specific setting or context (strong recommendation). Ideally, the screening instrument should exclude disability as part of the screening process. For individuals screened as positive for frailty, a more comprehensive clinical assessment should be performed to identify signs and underlying mechanisms of frailty (strong recommendation).Recommendations for ManagementA comprehensive care plan for frailty should address polypharmacy (whether rational or nonrational), the management of sarcopenia, the treatable causes of weight loss, and the causes of exhaustion (depression, anaemia, hypotension, hypothyroidism, and B12 deficiency) (strong recommendation). All persons with frailty should receive social support as needed to address unmet needs and encourage adherence to a comprehensive care plan (strong recommendation). First-line therapy for the management of frailty should include a multi-component physical activity programme with a resistance-based training component (strong recommendation). Protein/caloric supplementation is recommended when weight loss or undernutrition are present (conditional recommendation). No recommendation was given for systematic additional therapies such as cognitive therapy, problem-solving therapy, vitamin D supplementation, and hormone-based treatment. Pharmacological treatment as presently available is not recommended therapy for the treatment of frailty.

International audience

Objectives: To assess the prognostic significance of various characteristics and measurements of sarcopenia and physical functioning on all-cause mortality among home-dwelling older people with or at-risk of sarcopenia. Design: Cross-sectional and longitudinal analyses. Setting: Porvoo sarcopenia trial in open care. Participants: Community-dwelling people aged 75 and older (N = 428, of which 182 were re-examined at one year) with four years of follow-up. Measurements: Body mass index (BMI), physical functioning (physical component of the RAND-36) and physical performance tests (Short Physical Performance Battery (SPPB)), hand grip strength, walking speed, Charlson Comorbity Index, bioimpedance-based surrogates for muscle mass: Single Frequency Skeletal Muscle Index (SF-SMI), and Calf Intracellular Resistance Skeletal Muscle Index (CRi-SMI). Date of death was retrieved from central registers. Survival analyses were performed using Life-Table analyses and Cox models. Results: Most test variables (except BMI) were associated with four-year mortality in a dose-dependent fashion. After controlling for age, gender and co-morbidity, physical performance and functioning (both SPPB and RAND36), muscle strength (hand grip strength) and CRi-SMI appeared to be independent mortality risk indicators (p

Introduction: Multidomain interventions, targeting multiple risk factors simultaneously, could be effective dementia prevention strategies, but may be burdensome and not universally acceptable. Methods: We studied adherence rates and predictors in the Finnish Geriatric Intervevntion Study to Prevent Cognitive Impairment and Disability and Multidomain Alzheimer Preventive Trial prevention trials, for all intervention components (separately and simultaneously). Finnish Geriatric Intervevntion Study to Prevent Cognitive Impairment and Disability participants received a 2-year multidomain lifestyle intervention (physical training, cognitive training, nutritional counseling, and cardiovascular monitoring). Multidomain Alzheimer Preventive Trial participants received a 3-year multidomain lifestyle intervention (cognitive training, physical activity counseling, and nutritional counseling) with either an omega-3 supplement or placebo. Results: Adherence decreased with increasing intervention complexity and intensity: it was highest for cardiovascular monitoring, nutritional counseling, and the omega-3 supplement, and lowest for unsupervised computer-based cognitive training. The most consistent baseline predictors of adherence were smoking and depressive symptoms. Discussion: Reducing participant burden, while ensuring that technological tools are suitable for older individuals, maintaining face-to-face contacts, and taking into account participant characteristics may increase adherence in future trials. (C) 2019 the Alzheimer's Association. Published by Elsevier Inc. All rights reserved.

International audience; The prevalence of arterial hypertension, particularly systolic hypertension, is constantly rising worldwide. This is mainly the clinical expression of arterial stiffening as a result of the population's aging. Chronic elevation in blood pressure represents a major risk factor not only for cardiovascular morbidity and mortality but also for cognitive decline and loss of autonomy later in life. Clinical evidence obtained in community-dwelling older people with few comorbidities and preserved autonomy supports the beneficial effects of lowering blood pressure in older hypertensive subjects even after the age of 80 years. However, observational studies in frail older individuals treated for hypertension have shown higher morbidity and mortality rates compared with those with lower blood pressure levels. Clearly, in very old subjects, the therapeutic strategy of one size fits all cannot be applied because of the enormous functional heterogeneity in these individuals. Geriatric medicine proposes taking into account the function/frailty/autonomy status of older people. In the present review, we propose to adapt the antihypertensive treatment using an easy-to-apply visual numeric scale allowing the identification of 3 different patient profiles according to the functional status and autonomy for activities of daily living. For the preserved function profile, strategies should be those proposed for younger old adults. For the loss of function/preserved activities of daily living' profile, a more detailed geriatric assessment is needed to define the benefit/risk balance as well as requirements for the tailoring of the various therapeutic strategies. Lastly, for the loss of function and altered activities of daily living' profile, therapeutic strategies should be thoroughly reassessed, including deprescribing (when considered appropriate). In the near future, controlled trials are necessary for the most frail older subjects (ie, in those systematically excluded from previous clinical trials) to gain stronger evidence regarding the benefits of the various therapeutic strategies.

Background Active and healthy aging (AHA) is an important phenomenon in aging societies. Aims Our aim was to investigate midlife predictors of AHA in a socioeconomically homogenous male cohort. Methods In 2010, AHA was defined in the Helsinki Businessmen Study (men born in 1919–1934) with six criteria: (1) being alive, (2) responding to the mailed survey, (3) no reported cognitive problems, (4) feeling of happiness, (5) no difficulties in activities of daily living (ADL), and (6) no significant chronic diseases. Midlife factors were assessed in 1974 (n = 1759, mean age 47 years). Of the survivors in 2010 (n = 839), 10.0% (n = 84) fulfilled all AHA criteria, whilst 13.7% (n = 115) had chronic diseases but fulfilled other five criteria. Midlife predictors of AHA were analyzed with logistic models. Results Of the midlife factors, smoking [Odds ratio (OR) 0.44, 95% confidence interval (CI) 0.25–0.77], higher body mass index (BMI) (OR 0.75, 0.59–0.96), and higher total cholesterol (OR 0.76, 0.60–0.97) prevented significantly full AHA criteria, whereas higher self-rated health (SRH) (OR 1.73, 1.07–2.80) predicted significantly of fulfilling all AHA criteria. Midlife smoking (OR 0.87, 0.84–0.91), higher BMI (OR 0.73, 0.61–0.86), and higher alcohol consumption (OR 0.73, 0.60–0.90) prevented significantly of fulfilling the five AHA criteria with chronic diseases, and higher SRH (OR 1.90, 1.37–2.63) predicted significantly the five AHA criteria (chronic diseases present). Discussion Our study suggests that midlife factors, especially good SRH and low levels of cardiovascular risk factors, are associated with AHA. Conclusions The study emphasizes the importance of life-course predictors of healthy aging.

OBJECTIVES: Sarcopenia is associated with poor health outcomes. We examined the relative roles of muscle mass, strength, physical performance and obesity as health predictors among older sarcopenic people. DESIGN AND PARTICIPANTS: This prospective study examined community-dwelling people aged 75+ (N=262). SETTING: Porvoo Sarcopenia and Nutrition Trial. MEASUREMENTS: We collected demographic data and medical history by postal questionnaire including RAND-36 at baseline and at four years and measured BMI, Short Physical Performace Battery (SPPB), hand-grip strength, cognition and two surrogate measures of muscle mass; the Single Frequency Skeletal Muscle Index (SF-SMI) and the Calf Intracellular Resistance Skeletal Muscle Index (CRi-SMI). RESULTS: Adjusted for age and gender, independent outdoors mobility was predicted positively by baseline physical functioning scores in RAND-36 (p

OBJECTIVES To explore how neuropsychiatric symptoms (NPS) are associated with number of falls and how exercise modifies the risk of falling in community‐dwelling people with Alzheimer's disease (AD) and NPS. DESIGN Secondary analysis of a randomized controlled trial. SETTING Community. PARTICIPANTS Community‐dwelling individuals with AD (N=210) who completed the Neuropsychiatric Inventory (NPI) (N = 179). INTERVENTION Participants were randomized into 3 groups: group‐based exercise (4‐hour sessions with approximately 1 hour of training) and tailored home‐based exercise (1 hour of training) twice a week for 1 year and a control group receiving usual community care. In this secondary analysis, we merged the home‐based and group‐based exercise groups and compared this group with the control group. MEASUREMENTS NPS were measured using the NPI at baseline, and spousal caregivers recorded falls in daily fall diaries during 1 year of follow‐up. RESULTS The number of falls increased linearly with NPI score in the control group. Fall rates were 1.48 (95% confidence interval (CI)=1.26–1.73) per person‐year in the intervention group and 2.87 (95% CI=2.43–3.35) in the control group. Adjusted for age, sex, Mini‐Mental State Examination (MMSE) score, and Short Physical Performance Battery (SPPB) score, incidence rate ratio (IRR) was 0.48 (95% Cl=0.39–0.60, p < .001). Main effects for fall rate were significant for group (p < .001) and NPI total (p < .02); the interaction effect was also significant (p = .009) (adjusted for sex, age, MMSE score, SPPB score, and psychotropic medication use). CONCLUSION Exercise may decrease the risk of falling in community‐dwelling individuals with AD and NPS. Future exercise trials should confirm this finding in participants with significant NPS. TRIAL REGISTRATION ACTRN12608000037303. J Am Geriatr Soc 66:2377–2381, 2018.

Objectives: In a 5-year multifactorial risk reduction intervention for healthy men with at least one cardiovascular disease (CVD) risk factor, mortality was unexpectedly higher in the intervention than the control group during the first 15-year follow-up. In order to find explanations for the adverse outcome, we have extended mortality follow-up and examined in greater detail baseline characteristics that contributed to total mortality. Design: Long-term follow-up of a controlled intervention trial. Setting: The Helsinki Businessmen Study Intervention Trial. Participants and Intervention: The prevention trial between 1974-1980 included 1,222 initially healthy men (born 1919-1934) at high CVD risk, who were randomly allocated into intervention (n=612) and control groups (n=610). The 5-year multifactorial intervention consisted of personal health education and contemporary drug treatments for dyslipidemia and hypertension. In the present analysis we used previously unpublished data on baseline risk factors and lifestyle characteristics. Main outcome measures: 40-year total and cause-specific mortality through linkage to nation-wide death registers. Results: The study groups were practically identical at baseline in 1974, and the 5-year intervention significantly improved risk factors (body mass index, blood pressure, serum lipids and glucose), and total CVD risk by 46% in the intervention group. Despite this, total mortality has been consistently higher up to 25 years post-trial in the intervention group than the control group, and converging thereafter. Increased mortality risk was driven by CVD and accidental deaths. Of the newly-analysed baseline factors, there was a significant interaction for mortality between intervention group and yearly vacation time (P=0.027): shorter vacation was associated with excess 30-year mortality in the intervention (hazard ratio 1.37, 95% CI 1.03-1.83, P=0.03), but not in the control group (P=0.5). This finding was robust to multivariable adjustments. Conclusion: After a multifactorial intervention for healthy men with at least one CVD risk factor, there has been an unexpectedly increased mortality in the intervention group. This increase was especially observed in a subgroup characterised by shorter vacation time at baseline. Although this adverse response to personal preventive measures in vulnerable individuals may be characteristic to men of high social status with subclinical CVD, it clearly deserves further investigation.

Objective: Recent genome-wide association studies (GWASs) have revealed new genetic variants behind self-reported individual circadian preference, a distinct biological trait that is fairly stable during adulthood. In this study we analyze whether these genetic variants associate with objectively measured sleep timing from childhood to adolescence, over a nine-year period, with self-reported circadian preference during late adolescence. Methods: The participants (N = 100, 61% girls) came from a community cohort from Finland born in 1998. Sleep midpoint was measured with actigraphy at 8, 12 and 17 years. Circadian preference was self-reported at the age of 17 years. Single nucleotide polymorphisms (SNPs) were extracted at 12 years of age from the Illumina OmniExpress Exome 1.2 bead array data. Weighted polygenic risk scores (PRSs) were calculated based on top SNPs from a recent GWAS for morningness-eveningness in an adult population. Results: The PRS for circadian preference towards morningness was associated with earlier sleep midpoint from childhood to adolescence. When the time points were analyzed separately, the association between genetic tendency towards morning preference and earlier sleep midpoint was strongest among the 17-year-olds. Furthermore, the shift towards later sleep rhythm from early to late adolescence was milder for those with a higher PRS for morning preference. PRS for morning preference was also associated with self-reported circadian preference towards morningness in late adolescence. Conclusion: Our results suggest that genetic variants found for circadian preference in adults are already associated with objective sleep timing during childhood and adolescence, and predict individual developmental sleep trajectories from childhood onwards. (C) 2018 Published by Elsevier B.V.

Background: Even before the onset of age-related diseases, obesity might be a contributing factor to the cumulative burden of oxidative stress and chronic inflammation throughout the life course. Obesity may therefore contribute to accelerated shortening of telomeres. Consequently, obese persons are more likely to have shorter telomeres, but the association between body mass index (BMI) and leukocyte telomere length (TL) might differ across the life span and between ethnicities and sexes. Objective: A collaborative cross-sectionalmeta-analysis of observational studies was conducted to investigate the associations between BMI and TL across the life span. Design: Eighty-seven distinct study samples were included in the meta-analysis capturing data from 146,114 individuals. Studyspecific age- and sex-adjusted regression coefficients were combined by using a random-effects model in which absolute [base pairs (bp)] and relative telomere to single-copy gene ratio (T/S ratio) TLs were regressed against BMI. Stratified analysis was performed by 3 age categories ("young": 18-60 y; "middle": 61-75 y; and "old": >75 y), sex, and ethnicity. Results: Each unit increase in BMI corresponded to a-3.99 bp (95% CI: -5.17, -2.81 bp) difference in TL in the total pooled sample; among young adults, each unit increase in BMI corresponded to a -7.67 bp (95% CI:-10.03,-5.31 bp) difference. Each unit increase in BMI corresponded to a -1.58 × 10-3 unit T/S ratio (0.16% decrease; 95% CI: -2.14 × 10-3, -1.01 × 10-3) difference in ageand sex-adjusted relative TL in the total pooled sample; among young adults, each unit increase in BMI corresponded to a -2.58 × 10-3 unit T/S ratio (0.26% decrease; 95% CI: -3.92 × 10-3, -1.25 × 10-3). The associations were predominantly for the white pooled population. No sex differences were observed. Conclusions: A higher BMI is associated with shorter telomeres, especially in younger individuals. The presently observed difference is not negligible. Meta-analyses of longitudinal studies evaluating change in body weight alongside change in TL arewarranted.

Purpose: Corticosteroid-binding globulin (CBG) transports glucocorticoids in blood. Variation in genes SERPINA6 encoding for CBG, SERPINA2 and SERPINAI (serpin family A member 6, 2, and 1) have been shown to influence morning plasma cortisol and CBG in adults. However, association of this genetic variation with diurnal and stress-induced salivary cortisol remain unknown. This study aims to investigate the effect of genetic variation in SERPINA6/2/1 loci on diurnal and stress-induced salivary cortisol in children. Methods: We studied 186, 8-year-old children with genome-wide genotyping. We generated weighted polygenic risk score (PRS) based on 6 genome-wide significant SNPs (rs11621961, rs11629171, rs7161521, rs2749527, rs3762132, rs4900229) derived from the CORNET meta-analyses. Salivary cortisol was measured across one day and in response to the Trier Social Stress Test for Children (TSST-C). Results: Mixed models, adjusted for covariates, showed that the PRS x sampling time interactions associated with diurnal (P

Personal values influence behavior and decision making, but their long-term associations with health-related quality of life (HRQoL), frailty, and mortality are less clear. We studied these associations from midlife to old age in a 26-year follow-up of the Helsinki Businessmen Study (HBS) cohort. In 1974, 1320 clinically healthy men (born 1919-1934) reported in a 12-item questionnaire their personal values. In 2000, a mailed questionnaire, including assessment of HRQoL with RAND-36 (SF-36) instrument, was sent to survivors, and 1025 men responded. In 2000, the presence of phenotypic frailty was assessed using modified Fried criteria including indicators of shrinking, physical weakness, exhaustion, and physical inactivity. Mortality through December 31, 2000 was verified from national registries. Using a factor analysis, the data of the 12-item questionnaire of personal values were loaded in 3 factors: valuing health ("Health"), enjoyable and varying life ("Enjoyment"), and comfort and work-oriented life ("Work-life-balance"). Adjusted for age, we found a significant positive association between valuing "Health" in midlife and RAND-36 domains of Physical functioning (p = .032) and Vitality (p = .005) in old age. "Health" also predicted less frailty (p = .008), and "Enjoyment" was associated with higher mortality (p = .017). Value priorities of men assessed in midlife had long-term associations with HRQoL and frailty in old age, and they may also predict mortality.

Background: Neuropsychiatric symptoms (NPS) are common in Alzheimer's disease (AD) and are associated with admission to institutional care. Current guidelines recommend non-pharmacological interventions as the first-line treatment for NPS. However, high-quality randomized studies focused on NPS are scarce. The objective here was to examine whether a regular and long-term exercise programme either at home or as a group-based exercise at an adult day care centre has beneficial effects on AD patients' NPS or permanent institutionalizations. Design, setting, and participants: A randomized, controlled trial with 210 community-dwelling AD patients. Intervention: Two types of intervention comprising (1) group-based exercise in day care centres (GE) and (2) tailored home-based exercise (HE), both twice a week for 12 months, were compared with (3) a control group (CG) receiving usual community care. Measurements: NPS were measured with the Neuropsychiatric Inventory (NPI) at baseline and 6 months, and depression with the Cornell Scale for Depression in Dementia (CSDD) at baseline and 12 months. Data on institutionalizations were retrieved from central registers. Results: No significant differences between the groups were detected in NPI at 6 months or in CSDD at 12 months when analyses were adjusted for age, sex, baseline Clinical Dementia Rating, and Functional Independence Measure. There was no difference in admissions to permanent institutional care between the groups. Conclusions: Regular, long-term exercise intervention did not decrease NPS in patients with AD. (C) 2017 Elsevier Masson SAS and European Union Geriatric Medicine Society. All rights reserved.

Background/aim: Deficiency of acetyl-L-carnitine (ALC) and L-carnitine (LC) appears to play a role in peripheral diabetic neuropathy, although the evidence in humans is still limited. We conducted a systematic review and meta-analysis investigating the effect of ALC on pain and electromyographic parameters in people with diabetic neuropathy. Methods: A literature search in major databases, without language restriction, was undertaken. Eligible studies were randomized controlled trials (RCTs) or pre-and post-test studies. The effect of ALC supplementation on pain perception and electromyographic parameters in patients with diabetic neuropathy was compared vs. a control group (RCTs). The effect of ALC/LC on electromyographic parameters were also calculated vs. baseline values. Standardized mean differences (SMD) and 95% confidence intervals (CIs) were used for summarizing outcomes. Results: Six articles, with a total of 711 diabetic participants, were included. Three RCTs (340 treated with ALC vs. 203 placebo and 115 with methylcobalamine) showed that ALC reduces pain perception (SMD = -0.45; 95% CI: -0.86 to -0.04; P = 0.03; I-2 = 85%). Compared to controls, ALC supplementation improved nerve conduction velocity and amplitude response for ulnar nerve (both sensory and motor component). Compared to baseline values, ALC/LC supplementation improved nerve conduction velocity for all the sensory and motor nerves (except ulnar and peroneal) investigated and the amplitude of all nerves. The onset of adverse events was generally limited to minor side effects. Conclusion: ALC appears to be effective in reducing pain due to diabetic neuropathy compared to active or placebo controls and improving electromyographic parameters in these patients. (C) 2017 Elsevier Masson SAS and European Union Geriatric Medicine Society. All rights reserved.

Earlier puberty, especially in girls, is associated with physical and mental disorders. Prenatal glucocorticoid exposure influences the timing of puberty in animal models, but the human relevance of those findings is unknown. We studied whether voluntary consumption of licorice, which contains glycyrrhizin (a potent inhibitor of placental 11β-hydroxysteroid dehydrogenase type 2, the "barrier" to maternal glucocorticoids), by pregnant women was associated with pubertal maturation (height, weight, body mass index for age, difference between current and expected adult height, Tanner staging, score on the Pubertal Development Scale), neuroendocrine function (diurnal salivary cortisol, dexamethasone suppression), cognition (neuropsychological tests), and psychiatric problems (as measured by the Child Behavior Checklist) in their offspring. The children were born in 1998 in Helsinki, Finland, and examined during 2009-2011 (mean age = 12.5 (standard deviation (SD), 0.4) years; n = 378). Girls exposed to high maternal glycyrrhizin consumption (≥500 mg/week) were taller (mean difference (MD) = 0.4 SD, 95% confidence interval (CI): 0.1, 0.8), were heavier (MD = 0.6 SD, 95% CI: 0.2, 1.9), and had higher body mass index for age (MD = 0.6 SD, 95% CI: 0.2, 0.9). They were also 0.5 standard deviations (95% CI: 0.2, 0.8) closer to adult height and reported more advanced pubertal development (P < 0.04). Girls and boys exposed to high maternal glycyrrhizin consumption scored 7 (95% CI: 3.1, 11.2) points lower on tests of intelligence quotient, had poorer memory (P < 0.04), and had 3.3-fold (95% CI: 1.4, 7.7) higher odds of attention deficit/hyperactivity disorder problems compared with children whose mothers consumed little to no glycyrrhizin (≤249 mg/week). No differences in cortisol levels were found. Licorice consumption during pregnancy may be associated with harm for the developing offspring.