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Purpose: To explore the combined effect of trends in older people on their future healthcare utilisation., Methods: A Delphi study consisting of two rounds was conducted. The heterogeneous expert panel (n = 16) in the field of elderly care rated the effect of combinations of trends in the Netherlands on the use of seven healthcare services: i.e. informal, home, general practitioner, acute, specialist, nursing home and mental health care. The percentage and direction of the overall consensus, for the different health services, and for three main trends were analysed., Results: Experts reached consensus in 57 of 92 ratings (62%). Taking into account the interaction between trends, they expected an extra increase for informal, home, and general practitioner care, but no additional effect of interaction for specialist and acute care. Combinations that included trends leading to less support were expected to lead to an extra increase in utilisation., Conclusions: Experts expect that interaction between trends will lead to an extra increase in the use of general practitioner, home, and informal care. This increase is mainly the result of interaction with trends leading to less support for older persons. The present results show the need to take the effect of interaction into account when designing new health policy and in research on future healthcare utilisation., (Copyright © 2019 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Clinical medication reviews (CMRs) are increasingly performed in older persons with multimorbidity and polypharmacy to reduce drug-related problems (DRPs). However, there is limited evidence that a CMR can improve clinical outcomes. Little attention has been paid to patients' preferences and needs. The aim of this study was to investigate the effect of a patient-centred CMR, focused on personal goals, on health-related quality of life (HR-QoL), and on number of health problems., Methods and Findings: This study was a randomised controlled trial (RCT) performed in 35 community pharmacies and cooperating general practices in the Netherlands. Community-dwelling older persons (≥70 years) with polypharmacy (≥7 long-term medications) were randomly assigned to usual care or to receive a CMR. Randomisation was performed at the patient level per pharmacy using block randomisation. The primary outcomes were HR-QoL (assessed with EuroQol [EQ]-5D-5L and EQ-Visual Analogue Scale [VAS]) and number of health problems (such as pain or dizziness), after 3 and 6 months. Health problems were measured with a self-developed written questionnaire as the total number of health problems and number of health problems with a moderate to severe impact on daily life. Between April 2016 and February 2017, we recruited 629 participants (54% females, median age 79 years) and randomly assigned them to receive the intervention (n = 315) or usual care (n = 314). Over 6 months, in the intervention group, HR-QoL measured with EQ-VAS increased by 3.4 points (95% confidence interval [CI] 0.94 to 5.8; p = 0.006), and the number of health problems with impact on daily life decreased by 12% (difference at 6 months -0.34; 95% CI -0.62 to -0.044; p = 0.024) as compared with the control group. There was no significant difference between the intervention group and control group for HR-QoL measured with EQ-5D-5L (difference at 6 months = -0.0022; 95% CI -0.024 to 0.020; p = 0.85) or total number of health problems (difference at 6 months = -0.30; 95% CI -0.64 to 0.054; p = 0.099). The main study limitations include the risk of bias due to the lack of blinding and difficulties in demonstrating which part of this complex intervention (for example, goal setting, extra attention to patients, reducing health problems, drug changes) contributed to the effects that we observed., Conclusions: In this study, we observed that a CMR focused on personal goals improved older patients' lives and wellbeing by increasing quality of life measured with EQ-VAS and decreasing the number of health problems with impact on daily life, although it did not significantly affect quality of life measured with the EQ-5D. Including the patient's personal goals and preferences in a medication review may help to establish these effects on outcomes that are relevant to older patients' lives., Trial Registration: Netherlands Trial Register; NTR5713., Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: SV, HFK, and MB declare that their institution received unconditional grants from KNMP and Service Apotheek for the PhD project of SV, which this study is part of. JB and JG declare that they have no competing interests.

Background: Anxiety is among the most prevalent and disabling mental health problems in older adults. Few older adults with mild to moderately severe anxiety symptoms receive adequate interventions, putting them at risk for developing anxiety disorders, depression, and various somatic problems. Effective, low-threshold interventions should be developed. Blended care, in which a web-based intervention is combined with a limited amount of face-to-face contacts with a mental healthcare counselor at the general practice, is a promising option. The online self-help intervention "Living to the Full"-an Acceptance and Commitment Therapy (ACT) intervention-has been proven to reduce depression and anxiety in several patient groups, but has not yet been investigated in older adults. The aim of this study is to evaluate the (cost-)effectiveness of a blended form of "Living to the Full" in reducing anxiety symptoms in adults aged 55 to 75 years. Furthermore, moderators and mediators of the treatment effect are investigated., Methods/design: The (cost-)effectiveness of the ACT intervention will be investigated in a cluster single-blind randomized controlled trial (RCT). The blended intervention will be compared to treatment-as-usual. Thirty-six mental health counselors working at general practices in the Netherlands will be randomized to deliver blended care or treatment as usual. A total of 240 participants (aged 55-75 years) with mild to moderately severe anxiety complaints (defined as a total score of 5-15 on the GAD-7) will be recruited. There are four measurements consisting of online questionnaires (primary outcome: GAD-7) and a telephone interview: before the start of the intervention; directly following the intervention (14 weeks after baseline); and six and twelve months after baseline. Possible mediator variables will be assessed multiple times basis during the intervention., Discussion: This RCT will evaluate the effectiveness of a blended ACT intervention for older adults with anxiety symptoms. If the intervention is shown to be effective, it will be implemented, thereby improving the accessibility and quality of preventive interventions for older adults with anxiety problems., Trial Registration: Netherlands Trial Register, NTR6270 . Registered on 21 March 2017.

Background: the appropriateness of lowering systolic blood pressure remains controversial in the oldest-old. We tested whether systolic blood pressure is associated with all-cause mortality and change in cognitive function for patients prescribed antihypertensive treatment and those without treatment., Methods: we studied participants in the population-based Leiden 85-plus cohort study. Baseline systolic blood pressure and use of antihypertensive treatment were predictors; all-cause mortality and change in cognitive function measured using the Mini-Mental State Examination were the outcomes. Grip strength was measured as a proxy for physical frailty. We used Cox proportional hazards and mixed-effects linear regression models to analyse the relationship between systolic blood pressure and both time to death and change in cognitive function. In sensitivity analyses, we excluded deaths within 1 year and restricted analyses to participants without a history of cardiovascular disease., Results: of 570 participants, 249 (44%) were prescribed antihypertensive therapy. All-cause mortality was higher in participants with lower blood pressure prescribed antihypertensive treatment (HR 1.29 per 10 mmHg lower systolic blood pressure, 95% CI 1.15-1.46, P < 0.001). Participants taking antihypertensives showed an association between accelerated cognitive decline and lower blood pressure (annual mean change -0.35 points per 10 mmHg lower systolic blood pressure, 95% CI -0.60, -0.11, P = 0.004); decline in cognition was more rapid in those with lower hand grip strength. In participants not prescribed antihypertensive treatment, no significant associations were seen between blood pressure and either mortality or cognitive decline., Conclusions: lower systolic blood pressure in the oldest-old taking antihypertensives was associated with higher mortality and faster decline in cognitive function., (© The Author(s) 2018. Published by Oxford University Press on behalf of the British Geriatrics Society. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Cognitive and physical impairment frequently co-occur in older people. The aim of this study was to assess the temporal order of these age-related changes in cognitive and physical performance and to assess whether a relationship was different across specific cognitive and physical domains and age groups., Methods: Cognitive domains included global, executive, and memory function; physical domains included gait speed and handgrip strength. These domains were assessed in two population-based longitudinal cohorts covering the age ranges of 55-64, 65-74, 75-85, and 85-90 years with a follow-up of 5-12 years. Cross-lagged panel models were applied to assess the temporal relationships between the different cognitive and physical domains adjusting for age, sex, education, comorbidity, depressive symptoms, and physical activity., Results: Over all age groups, poorer executive function was associated with a steeper decline in gait speed (p < .05). From the age of 85 years, this relationship was found across all cognitive and physical domains (p < .02). From the age of 65 years, slower gait speed and/or weaker handgrip strength were associated with steeper declines in global cognitive function (p < .02), with statistically significant results across all cognitive domains in the age group of 75-85 years (p < .04)., Conclusions: The temporal relationship between cognitive and physical performance differs across domains and age, suggesting a specific rather than a general relationship. This emphasizes the importance of repeated measurements on different domains and encourages future research to the development of domain- and age-specific interventions., (© The Author 2016. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Impaired cardiac function has been related to accelerated cognitive decline in late-life., Objective: To investigate whether higher levels of high sensitivity cardiac troponin T (hs-cTnT), a sensitive marker for myocardial injury, are associated with worse cognitive function in the oldest old., Methods: In 455 participants of the population-based Leiden 85-plus Study, hs-cTnT was measured at 86 years. Cognitive function was measured annually during four years with the Mini-Mental State Examination (MMSE)., Results: Participants in the highest gender-specific tertile of hs-cTnT had a 2.0-point lower baseline MMSE score than participants in the lowest tertile (95% confidence interval (CI) (95% CI 0.73-3.3), and had a 0.58-point steeper annual decline in MMSE during follow-up (95% CI 0.06-1.1). The associations remained after adjusting for sociodemographic and cardiovascular risk factors excluding those without a history of overt cardiac disease., Conclusion: In a population-based sample of the oldest old, higher levels of hs-cTnT were associated with worse cognitive function and faster cognitive decline, independently from cardiovascular risk factors and a history of overt cardiac disease.

Purpose: Proactive care for community-dwelling older persons targeting self-reported hindering health complaints might prevent a decline in function. We investigated the spectrum of self-reported hindering complaints of community-dwelling older persons, the association with functional outcomes, and help-seeking behavior for these complaints., Methods: Within the ISCOPE trial, participants (aged ≥75 years) received the ISCOPE screening questionnaire, including the open-ended question "At the moment, which health complaints limit you the most in your day-to-day life?". After coding the answers with the ICPC-1-NL, we examined the prevalence and the association between the number and type of complaints and functional outcomes (Groningen Activities Restriction Scale, quality of life measured on Cantril's Ladder, Mini-Mental State Examination, Geriatric Depression Scale-15, and De Jong Gierveld Loneliness Scale). Electronic patient registers were searched for the most reported complaints., Results: 7285 participants (median age: 81.0 years [IQR 77.8-85.3], 38.6% males) reported 13,524 hindering complaints (median 1, range 0-18); 32.7% reported no complaints. Participants mostly reported problems with walking/standing (22.1%), pain (20.8%) or weakness/tiredness (8.5%). These complaints were mentioned in the electronic patient registers in 28.3%, 91.3% and 55.5%, respectively. Higher numbers of hindering complaints were related to poorer scores on the number of domains with problems, Cantril's Ladder for quality of life, Groningen Activities Restriction Scale, Geriatric Depression Scale, and De Jong Gierveld Loneliness Scale. Self-reported weakness, problems with walking/standing, visual limitations, cognitive problems, dyspnea and back complaints were associated with poorer scores on the number of domains with problems, Groningen Activities Restriction Scale, MMSE or Geriatric Depression Scale., Conclusion: One third of the participants reported no hindering complaints. Problems with walking/standing, pain, and weakness/tiredness were most reported, but not always found in electronic patient registers. A higher number of, and specific self-reported hindering complaints, were associated with poorer scores on functional outcomes. It may be helpful for general practitioners to ask about these complaints and their influence on daily life.

Background: Prevalence estimates of thyroid dysfunction and chronic kidney disease both increase with age. The aim of this study was to investigate the cross-sectional association between low thyroid function and renal function in subjects aged 85 years and to assess whether a low thyroid function at age 85 years is associated with an accelerated decline in renal function during follow-up., Methods: We included 558 participants from the Leiden 85-plus Study. At baseline (age 85 y), TSH, free T4 (fT4), and free T3 levels were measured. Thyroid function groups were created using clinical cutoff values of TSH and fT4. Serum creatinine concentrations were determined at baseline and annually during a 5-year follow-up period. Estimated glomerular filtration rates (eGFRs) were calculated by means of the Modification of Diet in Renal Disease Study equation., Results: At baseline, subjects with higher levels of TSH and lower levels of fT4 and free T3 had lower renal function. Participants with hypothyroidism [mean 53.7 (2.0) mL/min per 1.73 m(2))] and subclinical hypothyroidism [55.7 (2.1) mL/min per 1.73 m(2)] had lower mean eGFRs (SE) than participants with normal thyroid function [59.5 (0.7) mL/min per 1.73 m(2)]; the highest eGFR was observed in participants with hyperthyroidism [eGFR 61.5 (3.1) mL/min per 1.73 m(2)] (P for trend = .004). There was no association between thyroid hormone levels at baseline and the change in renal function during follow-up., Conclusions: Although low thyroid function was associated with lower renal function at age 85 years, an association between a low thyroid function and change in renal function over time was absent. Our findings question the causal relevance of the thyroid status for the deterioration of renal function in the oldest old.

In the aging society, it is important to identify very old persons at high risk of functional decline, cardiovascular disease and mortality. However, traditional risk markers lose their predictive value with age. We investigated whether plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels predict change in functional status, cardiovascular morbidity and mortality in very old age. Here we present an observational prospective cohort study (Leiden 85-plus Study, 1997-2004) in a population-based sample of 560 individuals aged 85 years with a 5-year complete follow-up for functional status, cardiovascular morbidity and cause-specific mortality. Median NT-proBNP for men was 351 pg/ml (cutoff values for low-medium tertiles 201 pg/ml and medium-high tertiles 649 pg/ml) and, for women, 297 pg/ml (cutoffs 204 and 519 pg/ml, respectively). During the 5-year follow-up, participants with high NT-proBNP had an accelerated cognitive decline and increase of activities of daily living (ADL) disability over time (all at p < 0.01) and an increased risk of incident heart failure [hazard ratio (HR) 3.3 (95 % confidence interval (CI) 1.8-6.1)], atrial fibrillation [HR 4.1 (2.0-8.7)], myocardial infarction [HR 2.1 (1.2-3.7)], stroke [HR 3.4 (1.9-6.3)], cardiovascular mortality [HR 5.5 (3.1-10)], non-cardiovascular mortality [HR 2.0 (1.4-3.0)] and all-cause mortality [HR 2.9 (2.1-4.0)], independent of other known risk markers. All results remained similar after exclusion of participants with heart failure at baseline. In very old age, high-NT-proBNP levels predict accelerated cognitive and functional decline, as well as cardiovascular morbidity and mortality. Results suggest that NT-proBNP can help clinicians to identify very old people at high risk of functional impairment and incident cardiovascular morbidity.

Objective: To investigate the relationship between apathy and perceived quality of life in groups both with and without depressive symptoms or cognitive impairment., Methods: We conducted a cross-sectional study comparing quality of life in older persons with and without apathy in 19 Dutch general practices. Participants were 1,118 older persons aged at least 75 years without current treatment for depression and a Mini-Mental State Examination score of at least 19. Perceived quality of life was determined using Cantril's Ladder for overall quality of life, EuroQol (EQ)-5D thermometer for subjective health quality, and De Jong-Gierveld Loneliness questionnaire for perceived loneliness. Apathy was assessed with the Apathy Scale., Results: Of the 1,118 older persons, apathy was present in 122 (11%) of them. Overall, apathy was associated with having no work, lower level of education, presence of depressive symptoms, cognitive impairment, and decreased scores on all quality of life measures. Among the 979 (88%) older persons without depressive symptoms and cognitive impairment, apathy was present in 73 (7.5%) of them, showing similar associations as in the total population. In the 77 (7%) persons with cognitive impairment only, apathy was correlated to a lower score on the EQ-5D thermometer. However, in the 51 (5%) depressed persons without cognitive impairment, presence of apathy did not contribute to their decreased quality of life., Conclusion: Apathy frequently occurred in community-dwelling older persons, also in the absence of depressive symptoms and cognitive impairment. In them, apathy contributed to the perception of a diminished quality of life in various aspects of daily life., (Copyright © 2014 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.)

Sarcopenia is thought to play a major role in the functional impairment that occurs with old age. In clinical practice, sarcopenia is often determined by measuring handgrip strength. Here, we compared the lower limb quadriceps strength to the handgrip strength in their association with health outcomes in older adults in primary care. Our study population consisted of older adults (n = 764, 68.2% women, median age 83) that participated in the Integrated Systemic Care for Older People (ISCOPE) study. Participants were visited at baseline to measure quadriceps strength and handgrip strength. Data on health outcomes were obtained at baseline and after 12 months (including life satisfaction, disability in daily living, GP contact-time and hospitalization). Quadriceps strength and handgrip strength showed a weak association (β = 0.42 [95% CI 0.33-0.50]; R (2) = 0.17). Quadriceps strength and handgrip strength were independently associated with health outcomes at baseline, including quality of life, disability in daily living, GP contact-time, hospitalization, and gait speed. Combined weakness of the quadriceps and handgrip distinguished a most vulnerable subpopulation that presented with the poorest health outcomes. At follow-up, handgrip strength showed an association with quality of life (β = 0.05; P = 0.002) and disability in daily living (β = -0.5; P = 0.004). Quadriceps weakness did not further contribute to the prediction of the measured health outcomes. We conclude that quadriceps strength is only moderately associated with handgrip strength in an older population and that the combination of quadriceps strength and handgrip strength measurements may aid in the identification of older adults in primary care with the poorest health outcomes. In the prediction of poor health outcomes, quadriceps strength measurements do not show an added value to the handgrip strength.

Objective: we compared the self-reported medication adherence and knowledge of older patients receiving their drugs via multidose drug dispensing (MDD users) with patients receiving manually dispensed drugs (non-MDD users)., Methods: MDD users (≥ 65 years, ≥ 5 oral chronic drugs) were randomly selected from eight Dutch community pharmacies. Non-MDD users (≥ 5 oral chronic drugs) were matched on age and gender. Medication adherence was assessed by using the Medication Adherence Reporting Scale (MARS) and medication knowledge by asking the indication of drugs. Cognitive function was measured with Mini-Mental State Examination (MMSE) for a sub selection of patients., Results: the percentage of patients being adherent to all drugs was higher for MDD users (n = 119, 81%) compared with non-MDD users (n = 96, 58%, P < 0.001).The percentage of patients with adequate knowledge was lower for MDD users (40%) compared with non-MDD users (79%, P < 0.001). The differences in adherence were independent of knowledge and MMSE scores., Conclusion: this study shows that older patients receiving their drugs via MDD reported a higher medication adherence compared with patients receiving manually dispensed drugs, despite a lower knowledge and lower cognitive function among patients receiving MDD.

This study aimed to explore the prognosis of very old people depending on their cardiovascular disease (CVD) history. This observational prospective cohort study included 570 participants aged 85 years from the general population with 5-year follow-up for morbidity, functional status, and mortality. At baseline, participants were assigned to three groups: no CVD history, "minor" CVD (angina pectoris, transient ischemic attack, intermittent claudication, and/or heart failure), or "major" CVD (myocardial infarction [MI], stroke, and/or arterial surgery). Follow-up data were collected on MI, stroke, functional status, and cause-specific mortality. The composite endpoint included cardiovascular events (MI or stroke) and cardiovascular mortality. At baseline, 270 (47.4 %) participants had no CVD history, 128 (22.4 %) had minor CVD, and 172 (30.2 %) had major CVD. Compared to the no CVD history group, the risk of the composite endpoint increased from 1.6 (95 % confidence interval [CI], 1.1-2.4) for the minor CVD group to 2.7 (95 % CI, 2.0-3.9) for the major CVD group. Similar trends were observed for cardiovascular and all-cause mortality risks. In a direct comparison, the major CVD group had a nearly doubled risk of the composite endpoint (hazard ratio, 1.8; 95 % CI, 1.2-2.7), compared to the minor CVD group. Both minor and major CVD were associated with an accelerated decline in cognitive function and accelerated increase of disability score (all p < 0.05), albeit most pronounced in participants with major CVD. CVD disease status in very old age is still of important prognostic value: a history of major CVD (mainly MI or stroke) leads to a nearly doubled risk of poor outcome, including cardiovascular events, functional decline, and mortality, compared with a history of minor CVD.

Background: ageing is frequently accompanied by a higher incidence of infections and an increase in disability in activities of daily living (ADL)., Objective: this study examines whether clinical infections [urinary tract infections (UTI) and lower respiratory tract infections (LRTI)] predict an increase in ADL disability, stratified for the presence of ADL disability at baseline (age 86 years)., Design: the Leiden 85-plus Study. A population-based prospective follow-up study., Setting: general population., Participants: a total of 154 men and 319 women aged 86 years., Methods: information on clinical infections was obtained from the medical records. ADL disability was determined at baseline and annually thereafter during 4 years of follow-up, using the 9 ADL items of the Groningen Activity Restriction Scale., Results: in 86-year-old participants with ADL disability, there were no differences in ADL increase between participants with and without an infection (-0.32 points extra per year; P = 0.230). However, participants without ADL disability at age 86 years (n = 194; 41%) had an accelerated increase in ADL disability of 1.07 point extra per year (P < 0.001). For UTIs, this was 1.25 points per year (P < 0.001) and for LRTIs 0.70 points per year (P = 0.041). In this group, an infection between age 85 and 86 years was associated with a higher risk to develop ADL disability from age 86 onwards [HR: 1.63 (95% CI: 1.04-2.55)]., Conclusions: among the oldest-old in the general population, clinically diagnosed infections are predictive for the development of ADL disability in persons without ADL disability. No such association was found for persons with ADL disability.

There are indications that in persons of older age, systolic blood pressure (SBP) is no longer associated with mortality. This raises the question whether the predictive value of SBP changes from younger to older age groups. Analysis in the Rotterdam Study, a population-based prospective cohort study among 4,612 participants aged ≥55 years without previous cardiovascular disease and with a median follow-up of 14.9 (interquartile range, 11.1-15.8) years. Within four age groups (55-64, 65-74, 75-84, ≥85 years), the predictive value of baseline SBP for mortality was studied. From age 55 to ≥85 years, risk of all-cause mortality associated with SBP ≥160 mmHg decreased from HR 1.7 (95%CI 1.2-2.2) to HR 0.7 (95%CI 0.4-1.1), p for trend <0.001. For participants with SBP 140-159 mmHg, the risk decreased from HR 1.2 (95%CI 0.9-1.5) to HR 0.7 (95%CI 0.5-1.1), p for trend <0.001. Analyses in the 5-year age groups showed an increased risk with higher SBPs up to age 75 years. After 75 years, a trend towards SBP no longer being associated with an increased mortality risk was seen in our study. These findings need to be considered with recently reported beneficial effects of antihypertensive treatment in this age group.

Background: Subclinical thyroid dysfunction has been implicated as a risk factor for cognitive decline in old age, but results are inconsistent. We investigated the association between subclinical thyroid dysfunction and cognitive decline in the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER)., Methods: Prospective longitudinal study of men and women aged 70-82 years with pre-existing vascular disease or more than one risk factor to develop this condition (N = 5,154). Participants taking antithyroid medications, thyroid hormone supplementation and/or amiodarone were excluded. Thyroid function was measured at baseline: subclinical hyper- and hypothyroidism were defined as thyroid stimulating hormones (TSH) <0.45 mU/L or >4.50 mU/L respectively, with normal levels of free thyroxine (FT4). Cognitive performance was tested at baseline and at four subsequent time points during a mean follow-up of 3 years, using five neuropsychological performance tests., Results: Subclinical hyperthyroidism and hypothyroidism were found in 65 and 161 participants, respectively. We found no consistent association of subclinical hyper- or hypothyroidism with altered cognitive performance compared to euthyroid participants on the individual cognitive tests. Similarly, there was no association with rate of cognitive decline during follow-up., Conclusion: We found no consistent evidence that subclinical hyper- or hypothyroidism contribute to cognitive impairment or decline in old age. Although our data are not in support of treatment of subclinical thyroid dysfunction to prevent cognitive dysfunction in later life, only large randomized controlled trials can provide definitive evidence.

Next to outer hair cell dysfunction, age-related hearing loss may be explained by apolipoprotein E (APOE) genotype. In the Leiden 85-plus Study, a population-based study, the participants were 85 years old. We measured hearing loss by pure-tone audiometry in 435 participants in relation to APOE. Results demonstrated that those with the APOE-ε4/ε4 genotype had the highest levels of hearing loss (n = 6; 56.1 dB), those with the APOE-ε3/ε4 or ε2/ε4 genotype (n = 89) had intermediate levels of hearing loss (51.0 dB), and those without the APOE-ε4 allele (n = 340) had the lowest levels of hearing loss (48.9 dB), p for trend = 0.02. Eighty percent of participants had hearing loss of 35 dB and more, that is, hearing impairment. The APOE-ε4 allele was associated with a 2.0-fold increased risk of hearing impairment (confidence interval [CI 95%], 1.0-4.0), compared with those without the APOE-ε4 allele. The risk for hearing impairment in subjects with the APOE-ε4 allele remained similar after adjustment for cardiovascular disease, stroke, and cognitive impairment. Our results suggest that the APOE-ε4 allele contributes to age-related hearing loss., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background: in older persons, anaemia is associated with a number of unfavourable outcomes. In approximately 30% of older persons with anaemia, the cause of the anaemia is unexplained. We assessed the clinical differences between subjects with explained and unexplained anaemia and investigated whether these subjects have different mortality patterns compared with subjects without anaemia., Design: observational prospective follow-up study., Setting: the Leiden 85-plus study., Participants: four hundred and ninety-one persons aged 86 years., Methods: the study population was divided in three groups: (i) no anaemia (reference group, n=377), (ii) explained anaemia (iron deficiency, folate deficiency, vitamin B12 deficiency, signs of myelodysplastic syndrome or renal failure, n=74) and (iii) unexplained anaemia, (n=40). Mortality risks were estimated with Cox-proportional hazard models., Results: haemoglobin levels were significantly lower in subjects with explained anaemia than in subjects with unexplained anaemia (P<0.01). An increased risk for mortality was observed in subjects with explained anaemia [HR: 1.93 (95% CI: 1.47-2.52), P<0.001], but not in subjects with unexplained anaemia [HR: 1.19 (95% CI: 0.85-1.69), P=0.31]. Adjusted analyses (sex, co-morbidity, MMSE, institutionalised and smoking) did not change the observed associations for both explained and unexplained anaemic subjects., Conclusion: older subjects with unexplained anaemia had similar survival compared with non-anaemic subjects. Increased mortality risks were observed in subjects with explained anaemia compared with non-anaemic subjects.

Objectives: to determine (cost)-effectiveness of a stepped-care intervention programme among subjects ≥ 75 years who screened positive for depressive symptoms in general practice., Design: the pragmatic cluster-randomised controlled trial with 12-month follow-up., Setting: sixty-seven Dutch general practices., Subjects: two hundred and thirty-nine subjects ≥ 75 years screened positive for untreated depressive symptoms (15-item Geriatric Depression Scale ≥ 5)., Methods: usual care (34 practices, 118 subjects) was compared with the stepped-care intervention (33 practices, 121 subjects) consisting of three steps: individual counselling; Coping with Depression course; and-if indicated-referral back to general practitioner to discuss further treatment. Measurements included severity of depressive symptoms [Montgomery-Åsberg Depression Rating Scale (MADRS)], quality of life, mortality and costs., Results: at baseline subjects mostly were mildly/moderately depressed. At 6 months MADRS scores had improved more in the usual care than the intervention group (-2.9 versus -1.1 points, P=0.032), but not at 12 months (-3.1 versus -4.6, P=0.084). No significant differences were found within two separate age groups (75-79 years and ≥ 80 years). In intervention practices, 83% accepted referral to the stepped-care programme, and 19% accepted course participation. The control group appeared to have received more psychological care., Conclusions: among older subjects who screened positive for depressive symptoms, an offered stepped-care intervention programme was not (cost)-effective compared with usual care, possibly due to a low uptake of the course offer., Trial Registration: www.controlled-trials.com/ISRCTN 71142851v.

Subclinical hypothyroidism is a common finding in older persons. Clinical guidelines are inconsistent in providing recommendations for the treatment of subclinical hypothyroidism, especially in older persons. To date, there is no high-quality evidence from randomized controlled trials about the effects of treatment of subclinical hypothyroidism in older persons. Any definitive recommendations on treatment should be based on data from large randomized placebo-controlled trials.

Background: reduced telomere length in blood cells has been associated with increased risk of multiple age-related diseases and is widely regarded as a general biomarker of ageing. Therefore, it is important to know both the extent and limitations of this association. We investigated the relation between telomere length and anaemia in two independent cohorts, with the prior expectation of adding anaemia to the list of conditions for which telomere reduction is a risk factor., Participants and Methods: the present study is embedded in the Newcastle 85-plus Study and Leiden 85-plus Study, two population-based studies of inhabitants of Newcastle and North Tyneside, UK (n = 749) and Leiden, the Netherlands (n = 658) aged 85 and over. High-molecular-weight DNA was isolated from full fresh blood (Newcastle) and peripheral blood mononuclear cells samples (Leiden). Telomere length was measured as abundance of telomeric template versus a single gene by quantitative real-time polymerase chain reaction. Anaemia was defined according to World Health Organization criteria., Results: in both studies, no differences in median telomere length were observed between participants with anaemia and participants without anaemia (Newcastle: 2,846 bp (interquartile range (IQR) 2,433-3,630) versus 2,920 bp (IQR 2,425-3,570), P = 0.63; Leiden: 4,136 bp (IQR 3,879-4,428) versus 4,167 bp (IQR 3,893-4,501), P = 0.41). Telomere length also did not correlate with any other haematological parameter in both men and women., Conclusions: in contrast to other age-related diseases, telomere length is not associated with anaemia or any other haematological parameter in older individuals in the general population.

Background: prevention of disability is an important aim of healthcare for older persons. Selection of persons at risk is a first crucial step in this process., Objectives: this study investigates the predictive value of multimorbidity for the development of disability in the general population of very old people and the role of cognitive impairment in this association., Design: the Leiden 85-plus Study (1997-2004) is an observational prospective cohort study with 5 years of follow-up., Setting: general population of the city of Leiden, the Netherlands., Subjects: population based sample of 594 participants aged 85 years., Methods: disability in activities of daily living (ADL) was measured annually for 5 years with the Groningen Activity Restriction Scale (range 9-36, 9 = optimal). Multimorbidity is defined as the presence of two or more chronic diseases at age 85 years. Cognitive function was measured at baseline with the mini-mental state examination (MMSE)., Results: at baseline participants with multimorbidity had higher ADL disability scores compared with those without [median 11 inter-quartile range (IQR 9-16) versus 9 (IQR 9-13) ADL points, Mann-Whitney U test P < 0.001]. Stratified into four MMSE groups, ADL disability increased over time in all groups, even in participants without multimorbidity (P trend <0.001). Multimorbidity predicted accelerated increase in ADL disability in participants with MMSE of 28-30 points (n = 205, 0.67 points/year, P < 0.001), but not in participants with lower MMSE scores (all P > 0.100)., Conclusion: the predictive value of multimorbidity for the increase in ADL disability varies with cognitive function in very old people. In very old people with good cognitive function, multimorbidity predicts accelerated increase in ADL disability. This relation is absent in very old people with cognitive impairment.

Background: The production of erythropoietin is triggered by impaired oxygen delivery to the kidney, either because of anemia or hypoxemia. High erythropoietin levels have been shown to predict the risk of death among patients with chronic heart failure. We investigated the prognostic value of elevated erythropoietin levels on mortality among very elderly people in the general population., Methods: The Leiden 85-plus Study is a population-based prospective follow-up study involving 599 people aged 85 years in Leiden, the Netherlands, enrolled between September 1997 and September 1999. Erythropoietin levels were determined at age 86. For this analysis, we included 428 participants with a creatinine clearance of at least 30 mL/min. Mortality data, recorded until Feb. 1, 2008, were obtained from the municipal registry., Results: During follow-up, 324 (75.7%) participants died. Compared with participants whose erythropoietin levels were in the lowest tertile (reference group), those whose levels were in the middle tertile had a 25% increased risk of death (hazard ratio [HR] 1.25, 95% confidence interval [CI] 0.95-1.64), and those whose levels were in the highest tertile had a 73% increased risk (HR 1.73, 95% CI 1.32-2.26) (p value for trend < 0.01). The association between erythropoietin levels and mortality remained largely unchanged after we adjusted for sex, creatinine clearance, hemoglobin level, comorbidity, smoking status and C-reactive protein level, and was similar for deaths from cardiovascular and noncardiovascular causes., Interpretation: Among people aged 85 years and older, elevated erythropoietin levels were associated with an increased risk of death, independent of hemoglobin levels.

Objectives: To determine the prospective relationship between blood pressure (BP) and cognitive function across a wide age range., Design: Prospective population-based cohort study., Setting: The Rotterdam Study and the Leiden 85-plus Study., Participants: Three thousand seventy-eight men and women, initial age 55 to 84 from the Rotterdam Study and 276 men and women, initial age 85, from the Leiden 85-plus Study., Measurements: Systolic BP (SBP) and diastolic BP (DBP) were measured at baseline, cognitive function was assessed at the end of follow-up using a dedicated neuropsychological test battery. The association between baseline BP levels and cognitive function later in life was assessed in 10-year age groups in the Rotterdam Study and in 85-year-olds of the Leiden 85-plus Study., Results: In the youngest participants (<65), SBP and DBP were not associated with cognitive function 11 years later. For persons aged 65 to 74, higher baseline SBP and DBP were related to worse cognitive function 11 years later. In contrast, in older age (> or = 75), higher SBP and DBP seemed to be related to better cognitive function at the end of follow-up. This effect appeared strongest in the highest age group (aged 85)., Conclusion: High BP was associated with greater risk of cognitive impairment in persons younger than 75 but with better cognitive function in older persons. Age-specific guidelines for BP management are needed, because the current directive that "lower is better" may not apply to BP levels in the very old.

Increased signaling of the pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) elicits apoptosis of skeletal muscle cells in various animal models. Within a population-based prospective follow up study of elderly people aged 85 years we show that a high innate production capacity of TNF-alpha precedes a steeper decline in muscle strength over time.

The association between inflammation and neuropsychiatric symptoms in old age is generally accepted but poorly understood. The purpose of this study was to examine whether inflammation precedes depressive symptoms and cognitive decline in old age, and to identify specific inflammatory pathways herein. We measured serum C-reactive protein (CRP) and lipopolysaccharide-induced production of Interleukin (IL)-1beta, IL-6, Tumor Necrosis Factor (TNF)-alpha, IL-1 receptor antagonist (ra), and IL-10 levels in 85-year-old participants free from neuropsychiatric symptoms at baseline (n=267). Participants were prospectively followed for depressive symptoms (Geriatric Depression Scale) and cognitive functioning (Mini Mental State Examination) from 85 to 90 years. Higher baseline CRP levels preceded accelerated increase in depressive symptoms (p<0.001). A higher production capacity of the pro-inflammatory cytokine IL-1beta preceded a greater increase of depressive symptoms (p=0.06), whereas that of its natural antagonist IL-1ra preceded a smaller increase of depressive symptoms (p=0.003). There was no relation of CRP, IL-1beta, and IL-1ra with cognitive decline. Our findings show that in old age inflammatory processes contribute to the development of depressive symptoms but not cognitive decline. A high innate IL-1ra to IL-1beta production capacity reflects a better ability to neutralize inflammation and may therefore protect against depressive symptoms.

It has been suggested in the literature that atherosclerosis is a common causal pathway of cognitive impairment and late-onset depression, which may explain their co-occurrence in old age. In both the 'Leiden 85-plus Study' and the literature, strong evidence is found for a causal relationship between atherosclerosis and cognitive impairment, but there is less evidence for a causal relationship between atherosclerosis and late-onset depression. In the 'Leiden 85-plus Study', cognitive impairment was a risk factor for the development of late-onset depression, but depression in old age did not predict cognitive decline. This means that the prevention of atherosclerosis might prevent cognitive impairment and hence late-onset depression in old age.

Aims/hypothesis: Diabetes mellitus is a risk factor for the development of cognitive impairment and dementia in the general population up to 75 years of age. As part of the Leiden 85-plus Study we studied the effects of diabetes on cognition in the oldest old., Subjects and Methods: The Leiden 85-plus Study is a prospective population-based study of 599 persons from age 85 onward. Cognitive function was assessed each year from ages 85 to 90 by means of four neuropsychological tests. The presence of diabetes and vascular disease was recorded at baseline, HbA(1c) was assessed by means of a blood sample at ages 85 and 90. The cross-sectional and prospective associations between diabetes and cognitive function were analysed with linear mixed models, adjusted for sex and level of education., Results: At age 85, diabetes was associated with a lower level of cognitive functioning on the Letter Digit Coding test and the Stroop Test. Diabetes was not associated with accelerated cognitive decline during follow-up. Within the group of diabetic patients, macrovascular disease was the most important determinant of cognitive dysfunction., Conclusions/interpretation: The association between diabetes and accelerated cognitive decline, which has been documented previously in patients up to 75 years of age, may be less evident after age 85. This suggests that the damage occurs in previous years and that therapies aimed at preventing cognitive decline and dementia should focus on the younger old.

Cross-sectional studies have repeatedly suggested peripheral blood monocyte telomere length as a biomarker of aging. To test this suggestion in a large population-based follow-up study of the oldest old, we measured telomere length at baseline in 598 participants of the Leiden 85-plus Study (mean age at baseline 89.8 years). We also obtained second telomere measurements from 81 participants after an average time span of between 3.9 and 12.9 years. Telomere length at baseline was not predictive for mortality (P > 0.40 for all-cause, cardiovascular causes, cancer or infectious diseases, Cox regression for gender-adjusted tertiles of telomere length) or for the incidence of dementia (P = 0.78). Longitudinally, telomere length was highly unstable in a large fraction of participants. We conclude that blood monocyte telomere length is not a predictive indicator for age-related morbidity and mortality at ages over 85 years, possibly because of a high degree of telomere length instability in this group.

Background: High concentrations of homocysteine and low concentrations of vitamin B-12 and folic acid are frequently observed in subjects with dementia., Objective: We assessed whether serum concentrations of homocysteine, vitamin B-12, or folic acid predict cognitive decline in old age., Design: This was a prospective, population-based, longitudinal study of 599 subjects (Leiden 85-Plus Study, Netherlands). The subjects were administered a battery of cognitive tests (including the Mini Mental State Examination, the Stroop test, a letter digit coding test, and a word recall test) at 85 y of age and yearly thereafter until 89 y of age. Serum concentrations of homocysteine, vitamin B-12, and folic acid were measured at 85 and 89 y of age. Cross-sectional associations between serum concentrations and cognition were assessed at 85 and 89 y of age. The association between baseline serum concentrations and subsequent longitudinal cognitive decline was assessed with the use of mixed linear models., Results: In the cross-sectional analyses, serum concentrations of homocysteine and folic acid were significantly associated with cognitive performance, but serum concentrations of vitamin B-12 were not. In the longitudinal analyses, there were no significant associations of serum concentrations of homocysteine, vitamin B-12, or folic acid with rate of cognitive decline., Conclusions: Elevated serum concentrations of homocysteine and reduced folic acid are associated with cognitive impairment in elderly persons but do not predict an increased rate of cognitive decline. The association of high serum concentrations of homocysteine and low folic acid with cognitive impairment in old age is likely to be a consequence of disease and not a contributory cause.

Purpose: To prospectively compare indicators of structural brain damage and total cerebral blood flow in patients with late-onset dementia, subjects of the same age with optimal cognitive function, and young subjects., Materials and Methods: The institutional ethics committee approved the studies, and all participants (or their guardians) gave informed consent. The test group included 17 patients older than 75 years (four men, 13 women; median age, 83 years) and with a diagnosis of dementia according to the criteria of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. The control group included 16 subjects (four men, 12 women; median age, 87 years) with optimal cognitive function, who were selected from among 599 elderly subjects enrolled in a population-based follow-up study, and 15 young healthy subjects (seven men, eight women; median age, 29 years). Measurements of intracranial and total brain volumes, structural brain damage, and cerebral blood flow were obtained with magnetic resonance imaging. Mean values were compared with the t test; medians, with the Mann-Whitney U test., Results: Values for total brain volume were significantly smaller in elderly subjects (P < .001) but did not differ significantly between patients with dementia and subjects of the same age with optimal cognitive function (P = .69). Among the elderly, significantly higher scores for number and extent of white matter areas of signal hyperintensity (P = .028) and lower magnetization transfer ratios (P = .016) indicated greater structural brain damage in those with dementia. Cerebral blood flow was 246 mL/min lower (P < .001) in elderly subjects than in young subjects. In patients with dementia, cerebral blood flow was 108 mL/min lower than that in subjects of the same age with optimal cognitive function (551 vs 443 mL/min, P < .001)., Conclusion: The combined observations of more structural brain damage and lower cerebral blood flow in demented elderly individuals than in subjects of the same age with optimal cognitive function support the hypothesis that vascular factors contribute to dementia in old age.

Background: Atherosclerosis may be linked to cognitive decline and depression in old age., Methods: The Leiden 85-Plus Study is a prospective population-based study of 599 subjects from age 85 onward. The generalized atherosclerotic burden was rated by the number of cardiovascular pathologies at baseline, as assessed by history taking from treating physicians and EKG. Cardiovascular pathologies included myocardial infarction, angina pectoris or myocardial ischemia, claudicatio intermittens, and arterial surgery. Global cognitive function (Mini-Mental State Examination), attention (Stroop Test), processing speed (Letter Digit Coding Test), immediate recall memory (Word Learning Test-Immediate Recall), delayed recall memory (Word Learning Test-Delayed Recall), and depressive symptoms (15-item Geriatric Depression Scale) were assessed each year from ages 85 through 90. The prospective associations between both the generalized atherosclerosis rating and stroke with cognitive function and depressive symptoms were analyzed by linear mixed models adjusted for sex and level of education., Results: During follow-up, there was a significant cognitive decline and a significant increase of depressive symptoms. At baseline, a history of stroke was correlated with lower global cognitive function, slower processing speed, impaired immediate and delayed recall memory, and more depressive symptoms. In addition, a higher generalized atherosclerosis rating was correlated with impaired global cognitive function, lower attention, and a slower processing speed at baseline. During follow-up, a higher generalized atherosclerosis rating was associated with an accelerated decline of immediate recall memory and delayed recall memory. In contrast, there was no relation between the generalized atherosclerosis rating and depressive symptoms, either in the cross-sectional analysis or in the prospective analysis., Conclusion: In the population at large, generalized atherosclerosis contributes to cognitive decline in old age but not to depression.

Aging is associated with an impaired capacity of the immune system to respond properly to danger signals, such as infection and cancer. Here, we provide evidence that an impaired innate immune response, as measured by a low production capacity of pro- and anti-inflammatory cytokines upon ex vivo standardized danger signalling with bacterial LPS, is predictive for frailty in elderly people: participants who at age 85-year produced low levels of LPS-induced IL-1beta, IL-6, TNF-alpha and IL-1Ra and IL-10, were found to have a more than 2-fold elevated overall mortality risk, independent of chronic illnesses (relative risk is 2.21, 95% confidence interval 1.27-3.82, P = 0.005), compared to peers with a higher production of any of the pro- and/or anti-inflammatory cytokines. A significant genetic association with the IL-10 promoter gene was found, indicating that people who are genetically predisposed low cytokine producers are at a higher risk of losing the capacity to respond properly to danger signals with aging. We conclude that a malfunctioning innate immune response predicts frailty in old age and is under specific (immuno-) genetic control., (Copyright 2004 Elsevier Inc.)

In view of the absolute and relative increase in the number of oldest old, it is important to identify the causes and consequences of disease in this group. One of the areas of focus in the 'Leiden 85-plus Study', a population-based prospective study amongst 85-year-olds in the Dutch town of Leiden, is therefore to study the causes and consequences of cognitive decline in the very elderly. Cognitive impairment is the main threat to independence in the oldest old; 85-year-old people with impaired cognitive function (prevalence: 35%) have a ten times greater risk of being limited in their activities of daily life. If this cognitive impairment could be prevented, a large proportion of the independence limitations in the general population could be prevented (population attributable risk: 70%). Limitations in cognitive functioning are strongly associated with the incidence of cardiovascular disease, as well as with a lower average HDL-cholesterol concentration and signs of inflammation. Vascular factors appear to be closely related to development of cognitive impairment in very elderly. Therefore, future therapeutic research will have to demonstrate to what extent influencing the cardiovascular risk factors can lead to the prevention of cognitive decline in the very elderly.

Background: Various studies support the notion that the clinical picture of depression in the oldest old differs from that in younger elderly. Moreover, withstanding the serious negative effects of depression on well being and functioning, the detection rate of depression in several medical settings is low., Methods: Prevalence of depression, correlates and the rate of recognition by general practitioners were assessed in an 85-year-old community-based population. The GDS-S was applied in 500 participants with a MMSE >18, from a representative sample of 599 community based 85-year-old subjects. Demographic data, daily functioning, health correlates, use of medication and recognition of depression were recorded in home visits and from the general practitioner and pharmacists registers., Results: The prevalence of depression, as measured with a GDS-S score of 5 points or more, was 15.4%, which is comparable to previous studies. No demographic factors were correlated with depression. Perceived health, loneliness, impaired mobility, cognitive decline and functional disability were major correlates of depression. From the participants who were seen by their general practitioner, 25% were recognised as depressed. Antidepressive pharmacotherapy was almost nonexistent., Limitations: Formal diagnosis of depression was not available. The data were collected cross-sectionally., Conclusions: Depression is highly prevalent in the oldest old and strongly associated with functional disability and cognitive impairment. It is important to enhance recognition of depression in community based oldest old as a first step to possible interventions.

Background: Successful aging is a worldwide aim, but it is less clear which indicators characterize elderly persons as successfully aged. We explored the meaning of successful aging from 2 perspectives., Methods: Analysis of data from the first cross-sectional part of the longitudinal Leiden 85-plus Study, conducted in Leiden, the Netherlands. All inhabitants of Leiden aged 85 years were eligible. Data were obtained from 599 participants (response rate, 87%). Successful aging from a public health perspective was defined as a state of being. All participants were classified as successful or not successful based on optimal scores for physical, social, and psychocognitive functioning and on feelings of well-being, using validated quantitative instruments. Qualitative indepth interviews on the perspectives of elderly persons were held with a representative group of 27 participants., Results: Although 45% (267/599) of the participants had optimal scores for well-being, only 13% (79/599) had optimal scores for overall functioning. In total, 10% (58/599) of the participants satisfied all the criteria and could be classified as successfully aged. The qualitative interviews showed that most elderly persons viewed success as a process of adaptation rather than a state of being. They recognized the various domains of successful aging, but valued well-being and social functioning more than physical and psychocognitive functioning., Conclusions: If successful aging is defined as an optimal state of overall functioning and well-being, only a happy few meet the criteria. However, elderly persons view successful aging as a process of adaptation. Using this perspective, many more persons could be considered to be successfully aged.

Objective: Limited formal education is associated with poor cognitive function. This could explain sex differences in cognitive function in the oldest old. Whether limited formal education explains differences in cognitive function between elderly women and men was explored., Methods: The Leiden 85-plus Study is a population based study investigating all 85 year old inhabitants of Leiden with an overall response rate of 87%. A sample of 599 participants were visited at their place of residence. The mini mental state examination was completed by all participants. Cognitive speed and memory were determined with four neuropsychological tests in participants with a mini mental state examination score higher than 18 points., Results: The proportion of women with limited formal education was significantly higher than that of men (70% v 53%, p=0.001), but women had better scores for cognitive speed and memory than men (p<0.05). After adjustment for differences in limited formal education and the presence of depressive symptoms, the odds ratio for women to have a higher cognitive speed than men was 1.7 (95% CI; 1.0 to 2.6), and for them to have a better memory the odds ratio was 1.8 (95%CI; 1.2 to 2.7)., Conclusion: Women have a better cognitive function than men, despite their lower level of formal education. Limited formal education alone, therefore, cannot explain the differences in cognitive function in women and men. These findings support the alternative hypothesis that biological differences, such as atherosclerosis, between women and men account for the sex differences in cognitive decline.

Objectives: To evaluate survival and causes of death in subjects with idiopathic senile gait disorders., Design: A population-based longitudinal study., Setting: Survival analysis of the oldest old within the Leiden 85-plus Study., Participants: We distinguished three different groups according to their gait: subjects with a normal gait (n = 25), subjects with senile gait disorders (n = 14), and subjects with gait disorders due to known disease (n = 87). The mean age was 90 years in all groups (range 87 to 97 years)., Measurements: The risk of all cause mortality and cardiovascular mortality was estimated over 5 years of follow-up in a Cox-proportional hazards model, adjusted for age and sex., Results: Eighty-nine of 126 subjects died during follow-up. Mean survival differed among the three groups (P log-rank = .01). All cause mortality risk was increased in subjects with senile gait disorders compared with subjects with a normal gait (RR = 2.8; 95% CI, 1.1-7.3, P = .03) and was similar to subjects with gait disorders caused by known disease (RR = 1.2; 95% CI: .6-2.5, P = .6). Mortality caused by cardiovascular disease also differed among the three groups (P log-rank = .03). The risk of cardiovascular death in subjects with senile gait disorders was twofold greater than in subjects with a normal gait (RR = 2.1; 95% CI, 0.4-10.3)., Conclusions: Senile gait disorders are related to subclinical, perhaps cardiovascular, disease. Senile gait disorders should not be accepted as an inevitable, benign concomitant of the normal aging process.

Summary: Objective: We investigated whether innate differences in cytokine response were associated with the absence of osteoarthritis (OA) in old age. Design: In 82 participants from a cross-sectional birth cohort, radiographs of hands, hips and knees were taken at the age of 90 years. OA was defined as a Kellgren–Lawrence score of at least two. “Free from OA” was defined at patient level as absence of hip and knee OA, and presence of OA in maximally two hand joints. The innate cytokine response was determined in whole-blood samples upon stimulation with lipopolysaccharide. Logistic regression analyses were used to investigate associations between absence of OA in relation to tertiles of interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α, IL-1 receptor antagonist (RA) and IL-10. Adjustments were made for gender and body mass index. Results: Sixteen percent of the participants were “free from OA”. Subjects in the lowest tertile of Il-1β production had a 11-fold increased chance to be free of OA [odds ratio (OR) 11.3, confidence intervals (CI) 95% 1.1–115.9], subjects in the lowest tertile of IL-6 production had an almost 7-fold increased chance to be free of OA (OR 6.7, 95% CI 1.1–41.2). Absence of hand OA was associated with low innate production of IL-6 and IL-1RA, absence of hip OA was associated with low innate IL-1β production. No associations were found for TNF-α and IL-10. Conclusions: Low innate capacity to produce the pro-inflammatory cytokines IL-1β and IL-6 is associated with the absence of OA in old age. [Copyright &y& Elsevier]