AgeWell.de – study protocol of a pragmatic multi-center cluster-randomized controlled prevention trial against cognitive decline in older primary care patients

Background In the absence of treatment options, the WHO emphasizes the identification of effective prevention strategies as a key element to counteract the dementia epidemic. Regarding the complex nature of dementia, trials simultaneously targeting multiple risk factors should be particularly effective for prevention. So far, however, only few such multi-component trials have been launched, but yielding promising results. In Germany, comparable initiatives are lacking, and translation of these complex interventions into routine care was not yet done. Therefore, AgeWell.de will be conducted as the first multi-component prevention trial in Germany which is closely linked to the primary care setting. Methods AgeWell.de will be designed as a multi-centric, cluster-randomized controlled multi-component prevention trial. Participants will be older community-dwelling general practitioner (GP) patients (60–77 years; n = 1,152) with increased dementia risk according to CAIDE (Cardiovascular Risk Factors, Aging, and Incidence of Dementia) Dementia Risk Score. Recruitment will take place at 5 study sites across Germany. GP practices will be randomized to either intervention A (advanced) or B (basic). GPs will be blinded to their respective group assignment, as will be the statistician conducting the randomization. The multi-component intervention (A) includes nutritional counseling, physical activity, cognitive training, optimization of medication, management of vascular risk factors, social activity, and, if necessary, further specific interventions targeting grief and depression. Intervention B includes general health advice on the intervention components and GP treatment as usual. We hypothesize that over the 2-year follow-up period the intervention group A will benefit significantly from the intervention program in terms of preserved cognitive function/delayed cognitive decline (primary outcome), and other relevant (secondary) outcomes (e.g. quality of life, social activities, depressive symptomatology, cost-effectiveness). Discussion AgeWell.de will be the first multi-component trial targeting risk of cognitive decline in older adults in Germany. Compared to previous trials, AgeWell.de covers an even broader set of interventions suggested to be beneficial for the intended outcomes. The findings will add substantial knowledge on modifiable lifestyle factors to prevent or delay cognitive decline. Trial registration German Clinical Trials Register (reference number: DRKS00013555)

Exploring the effect of multi-modal intervention against cognitive decline on atrophy and small vessel disease imaging markers in the AgeWell.de imaging study

BackgroundMultimodal lifestyle interventions might help to maintain healthy cognition in older age and to delay onset of dementia. Here, we studied the effects of a multi-modal lifestyle-based intervention, based on the FINGER trial, on magnetic resonance imaging (MRI) markers of hippocampal-limbic atrophy and cerebral small vessel disease in older adults at increased risk for dementia in Germany.MethodsLeipzig participants of the multicenter AgeWell.derandomized controlled trial were examined with magnetic resonance imaging before and after a two year intervention at 3 Tesla MRI. We extracted hippocampal volume and entorhinal cortex thickness (ECT), free water fraction (FW), peak width of skeletonized mean diffusivity (PSMD), white matter hyperintensity volume and mean gray matter cerebral blood flow and assessed the effect of the intervention on these imaging markers using linear mixed models. We also tested the effect of the intervention on the hippocampus-dependent Mnemonic Similarity Test and fixel-based white matter microstructure.Results56 individuals (mean(sd) age: 68.8 (4.2) years, 26 females, 24/32 intervention/control group) were included at baseline and 41 returned after an average of 28 months for the second assessment. ECT and FW exhibited stronger decline in the intervention compared to the control group in preregistered models but not when adjusted for baseline differences. All other markers progressed similarly across groups, however sample size was smaller than expected. In exploratory analyses, cerebral blood flow increased more in the intervention group and this change was associated with decreases in systolic blood pressure.ConclusionsIn this group of older adults at risk for dementia, we find no conclusive evidence whether a multi-modal lifestyle intervention improves brain imaging markers of neurodegeneration and small vessel disease. Preliminary evidence suggested an association of the intervention, increased cerebral blood flow and systolic blood pressure reductions

Association of mental demands in the workplace with cognitive function in older adults at increased risk for dementia

Objectives Growing evidence suggests a protective effect of high mental demands at work on cognitive function in later life. However, evidence on corresponding associations in older adults at increased risk for dementia is currently lacking. This study investigates the association between mental demands at work and cognitive functioning in the population of the AgeWell.de-trial. Methods Cross-sectional investigation of the association between global cognitive functioning (Montreal Cognitive Assessment) and mental demands at work in older individuals at increased risk for dementia (Cardiovascular Risk Factors, Aging, and Incidence of Dementia (CAIDE)score ≥ 9; n = 941, age: 60–77 years). Occupational information was matched to Occupational Information Network (O*NET)-descriptors. Associations between cognitive function and O*NET-indices executive, verbal and novelty were investigated using generalized linear models. Results Higher values of index verbal (b = .69, p = .002) were associated with better cognitive function when adjusting for covariates. No association was observed for indices executive (b = .37, p = .062) and novelty (b = .45, p = .119). Higher education, younger age, and employment were linked to better cognitive function, while preexisting medical conditions did not change the associations. Higher levels of depressive symptomatology were associated with worse cognitive function. Conclusions Higher levels of verbal demands at work were associated with better cognitive function for older adults with increased dementia risk. This suggests an advantage for older persons in jobs with high mental demands even after retirement and despite prevalent risk factors. Longitudinal studies are warranted to confirm these results and evaluate the potential of workplaces to prevent cognitive decline through increased mental demands

Effect of the frequently used antiepileptic drugs carbamazepine, gabapentin, and pregabalin on the pharmacokinetics of edoxaban and other oral factor xa inhibitors in healthy volunteers

PurposePregabalin, gabapentin, and carbamazepine, a potent inducer of cytochrome P450 (CYP) 3A4 and P-glycoprotein, are frequently used antiepileptic drugs that are often administered together with factor Xa inhibitors (FXaI). We aimed to investigate whether potentially clinically relevant drug-drug interactions occur with these combinations.MethodsIn an open-label fixed-sequence trial in 36 healthy volunteers, we evaluated the pharmacokinetics of 60 mg edoxaban and of a microdosed FXaI cocktail (25 µg apixaban, 50 µg edoxaban, and 25 µg rivaroxaban) before and during treatment with carbamazepine (12 evaluable volunteers, individually dosed to therapeutic concentrations), gabapentin (11 volunteers, titrated to 3 × 400 mg/d), and pregabalin (12 volunteers, titrated to 2 × 300 mg/d). The antiepileptics were dosed to steady-state and the CYP3A activity was evaluated by assessing the pharmacokinetics of microdosed midazolam (30 µg).ResultsCarbamazepine reduced the area under the plasma concentration-time curve (AUC∞) of 60 mg edoxaban by a factor of 0.48 (geometric mean ratio (GMR) with 90% CI (0.41–0.56); p < 0.0001) and Cmax by a factor of 0.47 (0.34–0.66) and reduced the exposure of the edoxaban metabolite M-4 to a similar extent. Carbamazepine also decreased the exposure (AUC∞) of microdosed apixaban, edoxaban, and rivaroxaban by a factor of 0.66, 0.59, and 0.56, respectively. Gabapentin and pregabalin did neither affect the exposure of 60 mg edoxaban nor the exposure of any microdosed FXaI.ConclusionCarbamazepine decreased FXaI exposure to a clinically relevant extent and dose adjustment may be required to maintain an adequate anticoagulant effect, whereas gabapentin and pregabalin do not require dose adjustment of FXaI

Recruitment and Baseline Characteristics of Participants in the AgeWell.de Study—A Pragmatic Cluster-Randomized Controlled Lifestyle Trial against Cognitive Decline

Targeting dementia prevention, first trials addressing multiple modifiable risk factors showed promising results in at-risk populations. In Germany, AgeWell.de is the first large-scale initiative investigating the effectiveness of a multi-component lifestyle intervention against cognitive decline. We aimed to investigate the recruitment process and baseline characteristics of the AgeWell.de participants to gain an understanding of the at-risk population and who engages in the intervention. General practitioners across five study sites recruited participants (aged 60–77 years, Cardiovascular Risk Factors, Aging, and Incidence of Dementia/CAIDE dementia risk score ≥ 9). Structured face-to-face interviews were conducted with eligible participants, including neuropsychological assessments. We analyzed group differences between (1) eligible vs. non-eligible participants, (2) participants vs. non-participants, and (3) between intervention groups. Of 1176 eligible participants, 146 (12.5%) dropped out before baseline; the study population was thus 1030 individuals. Non-participants did not differ from participants in key sociodemographic factors and dementia risk. Study participants were M = 69.0 (SD = 4.9) years old, and 52.1% were women. The average Montreal Cognitive Assessment/MoCA score was 24.5 (SD = 3.1), indicating a rather mildly cognitively impaired study population; however, 39.4% scored ≥ 26, thus being cognitively unimpaired. The bandwidth of cognitive states bears the interesting potential for differential trial outcome analyses. However, trial conduction is impacted by the COVID-19 pandemic, requiring adjustments to the study protocol with yet unclear methodological consequences

A multidomain intervention against cognitive decline in an at-risk-population in Germany: Results from the cluster-randomized AgeWell.de trial.

INTRODUCTION: We investigated the effectiveness of a multidomain intervention to preserve cognitive function in older adults at risk for dementia in Germany in a cluster-randomized trial. METHODS: Individuals with a Cardiovascular Risk Factors, Aging, and Dementia (CAIDE) risk score ≥ 9 aged 60 to 77 years were recruited. After randomization of their general practitioner (GP), patients received a multidomain intervention (including optimization of nutrition and medication, and physical, social, and cognitive activity) or general health advice and GP treatment as usual over 24 months. Primary outcome was global cognitive performance (composite z score, based on domain-specific neuropsychological tests). RESULTS: Of 1030 participants at baseline, n = 819 completed the 24-month follow-up assessment. No differences regarding global cognitive performance (average marginal effect = 0.010, 95% confidence interval: -0.113, 0.133) were found between groups at follow-up. Perceived restrictions in intervention conduct by the COVID-19 pandemic did not impact intervention effectiveness. DISCUSSION: The intervention did not improve global cognitive performance. HIGHLIGHTS: Overall, no intervention effects on global cognitive performance were detected. The multidomain intervention improved health-related quality of life in the total sample. In women, the multidomain intervention reduced depressive symptoms. The intervention was completed during the COVID-19 pandemic.fals

Predicting restoration of kidney function during CRRT-free intervals

<p>Abstract</p> <p>Background</p> <p>Renal failure is common in critically ill patients and frequently requires continuous renal replacement therapy (CRRT). CRRT is discontinued at regular intervals for routine changes of the disposable equipment or for replacing clogged filter membrane assemblies. The present study was conducted to determine if the necessity to continue CRRT could be predicted during the CRRT-free period.</p> <p>Materials and methods</p> <p>In the period from 2003 to 2006, 605 patients were treated with CRRT in our ICU. A total of 222 patients with 448 CRRT-free intervals had complete data sets and were used for analysis. Of the total CRRT-free periods, 225 served as an evaluation group. Twenty-nine parameters with an assumed influence on kidney function were analyzed with regard to their potential to predict the restoration of kidney function during the CRRT-free interval. Using univariate analysis and logistic regression, a prospective index was developed and validated in the remaining 223 CRRT-free periods to establish its prognostic strength.</p> <p>Results</p> <p>Only three parameters showed an independent influence on the restoration of kidney function during CRRT-free intervals: the number of previous CRRT cycles (medians in the two outcome groups: 1 vs. 2), the "Sequential Organ Failure Assessment"-score (means in the two outcome groups: 8.3 vs. 9.2) and urinary output after the cessation of CRRT (medians in two outcome groups: 66 ml/h vs. 10 ml/h). The prognostic index, which was calculated from these three variables, showed a satisfactory potential to predict the kidney function during the CRRT-free intervals; Receiver operating characteristic (ROC) analysis revealed an area under the curve of 0.798.</p> <p>Conclusion</p> <p>Restoration of kidney function during CRRT-free periods can be predicted with an index calculated from three variables. Prospective trials in other hospitals must clarify whether our results are generally transferable to other patient populations.</p

Fabrication Principles and Their Contribution to the Superior In Vivo Therapeutic Efficacy of Nano-Liposomes Remote Loaded with Glucocorticoids

We report here the design, development and performance of a novel formulation of liposome- encapsulated glucocorticoids (GCs). A highly efficient (>90%) and stable GC encapsulation was obtained based on a transmembrane calcium acetate gradient driving the active accumulation of an amphipathic weak acid GC pro-drug into the intraliposome aqueous compartment, where it forms a GC-calcium precipitate. We demonstrate fabrication principles that derive from the physicochemical properties of the GC and the liposomal lipids, which play a crucial role in GC release rate and kinetics. These principles allow fabrication of formulations that exhibit either a fast, second-order (t1/2 ∼1 h), or a slow, zero-order release rate (t1/2 ∼ 50 h) kinetics. A high therapeutic efficacy was found in murine models of experimental autoimmune encephalomyelitis (EAE) and hematological malignancies