An intriguing question with regard to ageing research is why some people age successfully and why others are burdened with chronic diseases and functional disability. Researchers aim to identify the candidate determinants associated with the preservation of vitality during a long life course.
In this thesis the study of candidate determinants of muscular and functional
vitality in a cohort of oldest old (85+) participants is described. The first part of this thesis focuses on the functional phenotype with handgrip strength, gait speed and functional ability as the parameters of this functional phenotype. The second part of this thesis focuses on candidate determinants of muscle weakness in oldest old people, such as blood pressure, insulin like growth factor-1, and cytokine production capacity.
The results of the studies in this thesis allow us to speculate about the predictive value of functional measurements as markers of vitality in a clinical population of oldest old patients. Use of these markers of vitality could contribute to increased vigilance in clinicians for increased risk of health problems in their very old patients. Furthermore, these vitality markers could be helpful in individual prognostication and decision making in very old patients who are faced with serious illnesses.
Aging is associated with progressive loss of muscle strength. Muscle tissue is vascularized by an elaborate vascular network. There is evidence that blood pressure (BP) is associated with muscle function in middle age. It is unknown how BP associates with muscle function in oldest old people. We studied the association between BP and handgrip strength in middle and old age.BP was measured automatically in middle-aged subjects and with a mercury sphygmomanometer in the oldest old. Handgrip strength was measured with a handgrip strength dynamometer. Cross-sectional measurements of handgrip strength and BP were available for 670 middle-aged subjects (mean 63.2 ± 6.6 years) and 550 oldest old subjects (all 85 years). Prospective data were available for oldest old subjects only with a 4-year follow-up at 89 years. The association between BP and handgrip strength was analyzed by linear regression analysis.In middle-aged subjects, BP and handgrip strength were not statistically significantly associated. In oldest old subjects, higher systolic BP (SBP), mean arterial pressure (MAP), and pulse pressure (PP) were associated with higher handgrip strength after adjusting for comorbidity and medication use (all P < 0.02). Furthermore, in oldest old subjects, changes in SBP, MAP, and PP after 4 years was associated with declining handgrip strength (all, P < 0.05).In oldest old, higher BP is associated with better muscle strength. Further study is necessary to investigate whether BP is a potential modifiable risk factor for prevention of age-associated decline in muscle strength.
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.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.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).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.
Abstract Background In many cases, life-sustaining treatment preferences are not timely discussed with older patients. Advance care planning (ACP) offers medical professionals an opportunity to discuss patients’ preferences. We assessed how often these preferences were known when older patients were referred to the emergency department (ED) for an acute geriatric assessment. Methods We conducted a descriptive study on patients referred to the ED for an acute geriatric assessment in a Dutch hospital. Patients were referred by general practitioners (GPs), or in the case of nursing home residents, by elderly care physicians. The referring physician was asked if preferences regarding life-sustaining treatments were known. The primary outcome was the number of patients for whom preferences were known. Secondary outcomes included which preferences, and which variables predict known preferences. Results Between 2015 and 2017, 348 patients were included in our study. At least one preference regarding life-sustaining treatments was known at referral in 45.4% (158/348) cases. In these cases, cardiopulmonary resuscitation (CPR) policy was always included. Preferences regarding invasive ventilation policy and ICU admission were known in 17% (59/348) and 10.3% (36/348) of the cases respectively. Known preferences were more frequent in cases referred by the elderly care physician than the GP ( P < 0.001). Conclusions In less than half the patients, at least one preference regarding life-sustaining treatments was known at the time of referral to the ED for an acute geriatric assessment; in most cases it concerned CPR policy. We recommend optimizing ACP conversations in a non-acute setting to provide more appropriate, desired, and personalized care to older patients referred to the ED.
Background This study reports the findings of the first large-scale Phase III investigator-driven clinical trial to slow the rate of cognitive decline in Alzheimer disease with a dihydropyridine (DHP) calcium channel blocker, nilvadipine. Nilvadipine, licensed to treat hypertension, reduces amyloid production, increases regional cerebral blood flow, and has demonstrated anti-inflammatory and anti-tau activity in preclinical studies, properties that could have disease-modifying effects for Alzheimer disease. We aimed to determine if nilvadipine was effective in slowing cognitive decline in subjects with mild to moderate Alzheimer disease. Methods and findings NILVAD was an 18-month, randomised, placebo-controlled, double-blind trial that randomised participants between 15 May 2013 and 13 April 2015. The study was conducted at 23 academic centres in nine European countries. Of 577 participants screened, 511 were eligible and were randomised (258 to placebo, 253 to nilvadipine). Participants took a trial treatment capsule once a day after breakfast for 78 weeks. Participants were aged >50 years, meeting National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer’s disease Criteria (NINCDS-ADRDA) for diagnosis of probable Alzheimer disease, with a Standardised Mini-Mental State Examination (SMMSE) score of ≥12 and <27. Participants were randomly assigned to 8 mg sustained-release nilvadipine or matched placebo. The a priori defined primary outcome was progression on the Alzheimer's Disease Assessment Scale Cognitive Subscale-12 (ADAS-Cog 12) in the modified intention-to-treat (mITT) population (n = 498), with the Clinical Dementia Rating Scale sum of boxes (CDR-sb) as a gated co-primary outcome, eligible to be promoted to primary end point conditional on a significant effect on the ADAS-Cog 12. The analysis set had a mean age of 73 years and was 62% female. Baseline demographic and Alzheimer disease–specific characteristics were similar between treatment groups, with reported mean of 1.7 years since diagnosis and mean SMMSE of 20.4. The prespecified primary analyses failed to show any treatment benefit for nilvadipine on the co-primary outcome (p = 0.465). Decline from baseline in ADAS-Cog 12 on placebo was 0.79 (95% CI, −0.07–1.64) at 13 weeks, 6.41 (5.33–7.49) at 52 weeks, and 9.63 (8.33–10.93) at 78 weeks and on nilvadipine was 0.88 (0.02–1.74) at 13 weeks, 5.75 (4.66–6.85) at 52 weeks, and 9.41 (8.09–10.73) at 78 weeks. Exploratory analyses of the planned secondary outcomes showed no substantial effects, including on the CDR-sb or the Disability Assessment for Dementia. Nilvadipine appeared to be safe and well tolerated. Mortality was similar between groups (3 on nilvadipine, 4 on placebo); higher counts of adverse events (AEs) on nilvadipine (1,129 versus 1,030), and serious adverse events (SAEs; 146 versus 101), were observed. There were 14 withdrawals because of AEs. Major limitations of this study were that subjects had established dementia and the likelihood that non-Alzheimer subjects were included because of the lack of biomarker confirmation of the presence of brain amyloid. Conclusions The results do not suggest benefit of nilvadipine as a treatment in a population spanning mild to moderate Alzheimer disease. Trial registration Clinicaltrials.gov NCT02017340, EudraCT number 2012-002764-27.
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