Association of Blood MicroRNA Expression and Polymorphisms with Cognitive and Biomarker Changes in Older Adults.

BACKGROUND: Identifying individuals before the onset of overt symptoms is key in the prevention of Alzheimer's disease (AD). OBJECTIVES: Investigate the use of miRNA as early blood-biomarker of cognitive decline in older adults. DESIGN: Cross-sectional. SETTING: Two observational cohorts (CHARIOT-PRO, Alzheimer's Disease Neuroimaging Initiative (ADNI)). PARTICIPANTS: 830 individuals without overt clinical symptoms from CHARIOT-PRO and 812 individuals from ADNI. MEASUREMENTS: qPCR analysis of a prioritised set of 38 miRNAs in the blood of individuals from CHARIOT-PRO, followed by a brain-specific functional enrichment analysis for the significant miRNAs. In ADNI, genetic association analysis for polymorphisms within the significant miRNAs' genes and CSF levels of phosphorylated-tau, total-tau, amyloid-ß42, soluble-TREM2 and BACE1 activity using whole genome sequencing data. Post-hoc analysis using multi-omics datasets. RESULTS: Six miRNAs (hsa-miR-128-3p, hsa-miR-144-5p, hsa-miR-146a-5p, hsa-miR-26a-5p, hsa-miR-29c-3p and hsa-miR-363-3p) were downregulated in the blood of individuals with low cognitive performance on the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). The pathway enrichment analysis indicated involvement of apoptosis and inflammation, relevant in early AD stages. Polymorphisms within genes encoding for hsa-miR-29c-3p and hsa-miR-146a-5p were associated with CSF levels of amyloid-ß42, soluble-TREM2 and BACE1 activity, and 21 variants were eQTL for hippocampal MIR29C expression. CONCLUSIONS: six miRNAs may serve as potential blood biomarker of subclinical cognitive deficits in AD. Polymorphisms within these miRNAs suggest a possible interplay between the amyloid cascade and microglial activation at preclinical stages of AD.

Implementation of dihydropyrimidine dehydrogenase deficiency testing in Europe.

BACKGROUND: The main cause for fluoropyrimidine-related toxicity is deficiency of the metabolizing enzyme dihydropyrimidine dehydrogenase (DPD). In 2020, the European Medicines Agency (EMA) recommended two methods for pre-treatment DPD deficiency testing in clinical practice: phenotyping using endogenous uracil concentration or genotyping for DPYD risk variant alleles. This study assessed the DPD testing implementation status in Europe before (2019) and after (2021) the release of the EMA recommendations. METHODS: The survey was conducted from 16 March 2022 to 31 July 2022. An electronic form with seven closed and three open questions was e-mailed to 251 professionals with DPD testing expertise of 34 European countries. A descriptive analysis was conducted. RESULTS: We received 79 responses (31%) from 23 countries. Following publication of the EMA recommendations, 87% and 75% of the countries reported an increase in the amount of genotype and phenotype testing, respectively. Implementation of novel local guidelines was reported by 21 responders (27%). Countries reporting reimbursement of both tests increased in 2021, and only four (18%) countries reported no coverage for any testing type. In 2019, major implementation drivers were 'retrospective assessment of fluoropyrimidine-related toxicity' (39%), and in 2021, testing was driven by 'publication of guidelines' (40%). Although the major hurdles remained the same after EMA recommendations-'lack of reimbursement' (26%; 2019 versus 15%; 2021) and 'lack of recognizing the clinical relevance by medical oncologists' (25%; 2019 versus 8%; 2021)-the percentage of specialists citing these decreased. Following EMA recommendations, 25% of responders reported no hurdles at all in the adoption of the new testing practice in the clinics. CONCLUSIONS: The EMA recommendations have supported the implementation of DPD deficiency testing in Europe. Key factors for successful implementation were test reimbursement and clear clinical guidelines. Further efforts to improve the oncologists' awareness of the clinical relevance of DPD testing in clinical practice are needed.

Iron Deficiency and Incident Infections among Community-Dwelling Adults Age 70 Years and Older: Results from the DO-HEALTH Study.

OBJECTIVES: To assess if baseline iron deficiency, with or without anemia, is associated with incident infections over 3 years among community-dwelling older adults. DESIGN: Prospective secondary analysis of DO-HEALTH, a 3-year randomized, double-blind controlled trial. SETTING AND PARTICIPANTS: 2157 community-dwelling adults age 70+ from 5 European countries with good cognitive function and mobility and no major health events in the 5 years prior to enrollment Measurements: Incident infections, their severity and type were recorded every 3 months throughout the 3-year follow-up. Iron deficiency was defined as soluble transferrin receptor (sTfR) levels > 28.1 nmol/l and anemia as hemoglobin levels < 120 g/l for women and 130 g/l for men. We applied negative binomial mixed effects regression models with random effects for countries, and controlling for treatment allocation, age, sex, body mass index, polypharmacy, number of comorbidities, smoking status, living situation, alcohol intake, frailty status, and physical activity levels. A pre-defined stratified analysis was performed to explore if the associations between iron deficiency and infections were consistent by baseline anemia status. RESULTS: In total, 2141 participants were included in the analyses (mean age 74.9 years, 61.5% of women, 26.8% with iron deficiency). Across all participants, baseline iron deficiency was not associated with incident overall infections, but was associated with a 63% greater rate of incident severe infections requiring hospitalization (incidence rate ratio [IRR] 1.63, 95% Confidence Interval [CI] 1.11-2.41, p=0.01). This association was more pronounced among the 2000 participants who did not have anemia at baseline (IRR=1.80, 95% CI 1.20-2.69, p=0.005). CONCLUSION: Based on this prospective study among generally healthy European community-dwelling older adults, iron deficiency was not associated with the incidence rate of overall infections but may increase the incidence of severe infections. Intervention studies are needed to prove the causality of this observation.

Prevalence of Physical Frailty: Results from the DO-HEALTH Study.

BACKGROUND: Frailty is a geriatric syndrome associated with multiple negative health outcomes. However, its prevalence varies by population and instrument used. We investigated frailty and pre-frailty prevalence by 5 instruments in community-dwelling older adults enrolled to a randomized-controlled trial in 5 European countries. METHODS: Cross-sectional baseline analysis in 2,144 DO-HEALTH participants recruited from Switzerland, Austria, France, Germany, and Portugal with complete data for frailty. Frailty status was assessed by the Physical Frailty Phenotype [PFP], SOF-Frailty Index [SOF-FI], FRAIL-Scale, SHARE-Frailty Instrument [SHARE-FI], and a modified SHARE-FI, and compared by country, age, and gender. Logistic regression was used to determine relevant factors associated with frailty and pre-frailty. RESULTS: Mean age was 74.9 (±4.4) years, 61.6% were women. Based on the PFP, overall frailty and pre-frailty prevalence was 3.0% and 43.0%. By country, frailty prevalence was highest in Portugal (13.7%) and lowest in Austria (0%), and pre-frailty prevalence was highest in Portugal (57.3%) and lowest in Germany (37.1%). By instrument and overall, frailty and pre-frailty prevalence was highest based on SHARE-FI (7.0% / 43.7%) and lowest based on SOF-FI (1.0% / 25.9%). Frailty associated factors were residing in Coimbra (Portugal) [OR 12.0, CI 5.30-27.21], age above 75 years [OR 2.0, CI 1.17-3.45], and female gender [OR 2.8, CI 1.48-5.44]. The same three factors predicted pre-frailty. CONCLUSIONS: Among relatively healthy adults age 70 and older enroled to DO-HEALTH, prevalence of frailty and pre-frailty differed significantly by instrument, country, gender, and age. Among instruments, the highest prevalence of frailty and pre-frailty was documented by the SHARE-FI and the lowest by the SOF-FI.