Neocortical Aβ-amyloid deposition, one of the hallmark pathologic features of Alzheimer's disease (AD), begins decades prior to the presence of clinical symptoms. As clinical trials move to secondary ...and even primary prevention, understanding the rates of neocortical Aβ-amyloid deposition and the age at which Aβ-amyloid deposition becomes abnormal is crucial for optimizing the timing of these trials. As APOE-ε4 carriage is thought to modulate the age of clinical onset, it is also important to understand the impact of APOE-ε4 carriage on the age at which the neocortical Aβ-amyloid deposition becomes abnormal. Here, we show that, for 455 participants with over 3 years of follow-up, abnormal levels of neocortical Aβ-amyloid were reached on average at age 72 (66.5–77.1). The APOE-ε4 carriers reached abnormal levels earlier at age 63 (59.6–70.3); however, noncarriers reached the threshold later at age 78 (76.1–84.4). No differences in the rates of deposition were observed between APOE-ε4 carriers and noncarriers after abnormal Aβ-amyloid levels had been reached. These results suggest that primary and secondary prevention trials, looking to recruit at the earliest stages of disease, should target APOE-ε4 carriers between the ages of 60 and 66 and noncarriers between the ages of 76 and 84.
•APOE-ε4 carriers reached abnormal levels of Aβ ~15 years earlier than noncarriers.•APOE-ε4 carriers and noncarriers had no differences in Aβ deposition rates beyond the threshold.•Primary and secondary prevention trials should target APOE-ε4 carriers aged between 60 and 66.•Primary and secondary prevention trials should target APOE-ε4 non-carriers aged between 76 and 84.
Abstract Background and Aims A cardiovascular disease polygenic risk score (CVD-PRS) can stratify individuals into different categories of cardiovascular risk, but whether the addition of a CVD-PRS ...to clinical risk scores improves the identification of individuals at increased risk in a real-world clinical setting is unknown. Methods The Genetics and the Vascular Health Check Study (GENVASC) was embedded within the UK National Health Service Health Check (NHSHC) programme which invites individuals between 40–74 years of age without known CVD to attend an assessment in a UK general practice where CVD risk factors are measured and a CVD risk score (QRISK2) is calculated. Between 2012–2020, 44,141 individuals (55.7% females, 15.8% non-white) who attended an NHSHC in 147 participating practices across two counties in England were recruited and followed. When 195 individuals (cases) had suffered a major CVD event (CVD death, myocardial infarction or acute coronary syndrome, coronary revascularisation, stroke), 396 propensity-matched controls with a similar risk profile were identified, and a nested case-control genetic study undertaken to see if the addition of a CVD-PRS to QRISK2 in the form of an integrated risk tool (IRT) combined with QRISK2 would have identified more individuals at the time of their NHSHC as at high risk (QRISK2 10-year CVD risk of ≥10%), compared with QRISK2 alone. Results The distribution of the standardised CVD-PRS was significantly different in cases compared with controls (cases mean score .32; controls, −.18, P = 8.28×10−9). QRISK2 identified 61.5% (95% confidence interval CI: 54.3%–68.4%) of individuals who subsequently developed a major CVD event as being at high risk at their NHSHC, while the combination of QRISK2 and IRT identified 68.7% (95% CI: 61.7%–75.2%), a relative increase of 11.7% (P = 1×10−4). The odds ratio (OR) of being up-classified was 2.41 (95% CI: 1.03–5.64, P = .031) for cases compared with controls. In individuals aged 40–54 years, QRISK2 identified 26.0% (95% CI: 16.5%–37.6%) of those who developed a major CVD event, while the combination of QRISK2 and IRT identified 38.4% (95% CI: 27.2%–50.5%), indicating a stronger relative increase of 47.7% in the younger age group (P = .001). The combination of QRISK2 and IRT increased the proportion of additional cases identified similarly in women as in men, and in non-white ethnicities compared with white ethnicity. The findings were similar when the CVD-PRS was added to the atherosclerotic cardiovascular disease pooled cohort equations (ASCVD-PCE) or SCORE2 clinical scores. Conclusions In a clinical setting, the addition of genetic information to clinical risk assessment significantly improved the identification of individuals who went on to have a major CVD event as being at high risk, especially among younger individuals. The findings provide important real-world evidence of the potential value of implementing a CVD-PRS into health systems.
Older men on an average have lower testosterone concentrations, compared with younger men, and more age-related comorbidities. Whether lower testosterone concentrations contribute to biological ...ageing remains unclear. Shorter telomeres are a marker for biological age. We tested the hypothesis that testosterone concentrations are associated with leucocyte telomere length (LTL), in middle- to older-aged men.
Cross-sectional analysis of the UK Biobank study, involving community-dwelling men aged 40-69 years.
Serum testosterone and sex hormone-binding globulin (SHBG) were assayed. Free testosterone was calculated (cFT). Leucocyte telomere length was measured using polymerase chain reaction. Multivariable models were used to assess associations of hormones with standardised LTL.
In 167 706 men, median age 58 years, adjusting for sociodemographic, lifestyle, and medical factors, total testosterone was inversely associated with standardised LTL, which was 0.09 longer (95% confidence interval CI, 0.08-0.10, P < .001) in men with total testosterone at median of lowest quintile Q1 vs highest Q5. This relationship was attenuated after additional adjustment for SHBG (0.03 longer, CI = 0.02-0.05, P = .003). The association between cFT and LTL was similar in direction but lower in magnitude. In multivariable analysis, SHBG was inversely associated with standardised LTL, which was 0.12 longer (CI = 0.10-0.13, P < .001) for SHBG at median Q1 vs Q5. Results were similar with testosterone included in the model (0.10 longer, CI = 0.08-0.12, P < .001).
Total testosterone and SHBG were independently and inversely associated with LTL. Men with higher testosterone or SHBG had shorter telomeres, arguing against a role for testosterone to slow biological ageing in men.
Colchicine reduces risk of cardiovascular events in patients post–myocardial infarction and in patients with chronic coronary disease. It remains unclear whether this effect is related to the time of ...onset of treatment following an acute coronary syndrome (ACS).
This study investigates risk for major adverse cardiovascular events in relation to history and timing of prior ACS, to determine whether the benefits of colchicine are consistent independent of prior ACS status.
The LoDoCo2 (Low-Dose Colchicine 2) trial randomly allocated patients with chronic coronary disease to colchicine 0.5 mg once daily or placebo. The rate of the composite of cardiovascular death, spontaneous myocardial infarction, ischemic stroke, or ischemia-driven coronary revascularization was compared between patients with no prior, recent (6-24 months), remote (2-7 years), or very remote (>7 years) ACS; interaction between ACS status and colchicine treatment effect was assessed.
In 5,522 randomized patients, risk of the primary endpoint was independent of prior ACS status. Colchicine consistently reduced the primary endpoint in patients with no prior ACS (incidence: 2.8 vs 3.4 events per 100 person-years; hazard ratio HR: 0.81; 95% confidence interval CI: 0.52-1.27), recent ACS (incidence: 2.4 vs 3.3 events per 100 person-years; HR: 0.75; 95% CI: 0.51-1.10), remote ACS (incidence: 1.8 vs 3.2 events per 100 person-years, HR: 0.55; 95% CI: 0.37-0.82), and very remote ACS (incidence: 3.0 vs 4.3 events per 100 person-years, HR: 0.70; 95% CI: 0.51-0.96) (P for interaction = 0.59).
The benefits of colchicine are consistent irrespective of history and timing of prior ACS. (The LoDoCo2 Trial: Low Dose Colchicine for secondary prevention of cardiovascular disease LoDoCo2 ACTRN12614000093684)
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Low-dose colchicine significantly reduces the risk of cardiovascular events in patients with chronic coronary disease. An increase of non-cardiovascular death raised concerns about its safety. This ...study reports cause-specific mortality and baseline predictors of mortality in the Low-Dose Colchicine 2 (LoDoCo2) trial.
Patients with chronic coronary disease were randomly allocated to colchicine 0.5 mg once daily or placebo on a background of optimal medical therapy. Cause-specific mortality data were analysed, stratified by treatment status. Multivariate analyses were performed to examine the predictors of mortality as well as cardiovascular and non-cardiovascular death.
After a median 28.6 months follow-up, 133 out of 5522 participants (2.4%) died. Forty-five deaths were cardiovascular (colchicine versus placebo: 20 0.7% versus 25 0.9%, HR, 0.80; 95% CI, 0.44–1.44), while eighty-eight deaths were non-cardiovascular (53 1.9% versus 35 1.3%; HR, 1.51; 95% CI, 0.99–2.31). Forty-eight deaths were due to cancer (26 0.9% versus 22 0.8%), thirteen end-stage pulmonary disease (9 0.3% versus 4 0.1%), eight infection (4 0.1% versus 4 0.1%), five dementia (4 0.1% versus 1 0.0%) and five related multiple organ failure (3 0.1% versus 2 0.1%). Multivariable analysis demonstrated age > 65 years was the only independent baseline characteristic associated with non-cardiovascular death (HR, 3.65; 95% CI, 2.06–6.47).
During the LoDoCo2 trial, assignment to colchicine was not associated with an adverse effect on any specific causes of death. Most deaths were related to non-cardiovascular causes, underscoring the importance of comorbidities as drivers of all-cause mortality in patients with chronic coronary disease.
•Low-dose colchicine significantly reduces the risk of cardiovascular events.•Low-dose Colchicine 2 trial showed a numeric increase in non-cardiovascular deaths.•Long-term colchicine treatment is not associated with any specific cause of death.•Of note, deaths by cancer and infection were equal between colchicine and placebo.•These results confirm the safety of long-term use of low-dose colchicine.
BACKGROUND The clinical course of patients with malignant pleural effusions (MPEs) varies. The decision to undertake “definitive therapy” (pleurodesis, indwelling pleural catheter IPC, or both) for ...MPEs is decided on a case-by-case basis. Identifying factors that predict definitive therapy may help guide early initiation of treatment. The aim of the study was to identify clinical, laboratory, and radiologic predictors associated with clinicians' prescription of definitive therapy for patients with MPE. METHODS A multicenter, observational study was conducted over 55 months involving tertiary centers in Perth, Western Australia, Australia, and Lleida, Spain. Demographic, clinical, radiologic, biochemical, and histologic data and the treatments received were recorded. Logistic regression was performed to determine the variables useful for predicting definitive therapy. RESULTS Data of 540 patients (365 from Perth and 184 from Lleida) were analyzed; 537 fulfilled the criteria of an MPE. Definitive therapy was used in 288 patients (53.6'): 199 received a pleurodesis and 89 an IPC. Univariate analysis of the combined cohort revealed that definitive therapy was more likely if the effusion has low pH, either as a continuous variable (OR, 30.30; P < .01) or with a pH cutoff of < 7.2 (OR, 2.09; P = .03); was large (> 50' of hemithorax) (OR, 2.75; P < .01); or was associated with mesothelioma (OR, 1.83; P < .01). Following multivariate analysis, low pleural pH (OR, 37.04; P < .01), large effusions (OR, 3.31; P < .01), and increasing age (OR 1.02, P = .01) were associated with the use of definitive therapy. CONCLUSIONS Patients with MPE with an effusion of low pleural fluid pH and large size on radiographs at first presentation are more likely to be treated with pleurodesis and/or IPC.
Evidence of the benefits of arts engagement to community wellbeing has been mounting since the 1990s. However, large scale, quantitative, epidemiological studies of the "arts-healthy aging" ...relationship, or the types of arts older adults voluntarily choose to engage in as part of their everyday life, for enjoyment, entertainment or as a hobby (vs. therapy or interventions) are limited. The aims of this study were to describe older adult recreational arts engagement via the Busselton Healthy Ageing Study (BHAS) cohort, and to determine if there was an association between arts engagement, general health and mental wellbeing.
Overall, 2,843 older adults (born 1946-1964) from the BHAS cohort (
= 5,107) who had completed a supplementary arts survey (
= 3,055, 60%) and had data on required variables were included in this study (93% of those eligible). The dependent variable was general health (SF12) and subjective mental wellbeing (Warwick-Edinburgh Mental Wellbeing Scale, WEMWBS). The independent variable was hours engaged in recreational arts in the last 12 months. A descriptive analysis followed by a linear regression analysis was conducted.
The prevalence of recreational arts engagement in the last 12 months was 85% (mean = 132 h/year). Older adults engaged in the arts in a number of ways including attending events (79%), actively participating/making art (40%), as an arts society/club/organization member (20%), by learning about the arts (13%) or by volunteering/working in the arts (non-professional, 11%). When general health was assessed via the SF12, the average physical component score (PCS) was 50.1 (SD 8.9) and the average mental component score (MCS) was 53.6 (SD 8.3). When mental wellbeing was assessed, the average WEMWBS score was 54.9 (SD = 8.6). After adjustment for 12 demographic and lifestyle covariates, it was found that older adults who engaged in any recreational arts in the last 12 months had significantly higher WEMWBS scores and higher SF12 physical component scores than those who did not engage in the arts (0 h/year).
Evidence of an arts-health relationship was found in this study. The suitability of the arts as a population based, healthy aging strategy to influence the mental wellbeing and general health of older adults should be investigated further.
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