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Study Objectives: The association of shift work (SW) and disrupted circadian rhythm with markers of large artery atherosclerosis and cerebral small vessel disease is uncertain. We aimed to study the separate association of current and former SW with these markers., Methods: We included participants from the population-based Hamburg City Health Study. SW was defined by monthly working hours between 06:00 pm and 07:00 am containing night shifts for at least 12 months. Cross-sectional data were obtained from structured questionnaires, laboratory analyses, physical examinations, brain magnetic resonance imaging, and carotid ultrasound. We performed multivariable regression analysis with carotid intima-media thickness (CIMT), and peak-width skeletonized mean diffusivity (PSMD) as dependent variables., Results: Three hundred and forty-four current, 238 former, and 7162 never-shift workers were included. The median age was 60 years for both current and former shift workers, and total duration of SW was comparable for the two groups. Current shift workers were less frequently female (27.3% vs. 44.5%; p  < .001), had more frequent hyperlipidemia (31.5% vs. 22.3%; p  = .024), and diabetes (16.2% vs. 3.2%; p  < .001). After adjustment for age and sex, reduced quality of sleep (β = 1.61, p  = .001) and low education (β = 2.63, p  < .001) were associated with current but not former SW. Adjusted for age and sex, the current SW was associated with higher CIMT (β = 0.02, p  = .001) and PSMD (β = 9.06e-06, p  = .006), whereas former SW was not. Adjusted for risk factors, current SW remained associated with PSMD (β = 9.91e-06, p  = .006) but not with CIMT., Conclusions: Current SW was associated with CIMT and with PSMD, with the latter association remaining after adjustment for risk factors. Former SW showed no associations with CIMT or PSMD. This may indicate that current SW is linked with increased neurovascular risk through disrupted circadian rhythms., Trial Registration Information: The trial was submitted at http://www.clinicaltrials.gov, under NCT03934957 on January 4, 2019. The first participant was enrolled in February 2016., (© The Author(s) 2024. Published by Oxford University Press on behalf of Sleep Research Society.)

The increasing global life expectancy brings forth challenges associated with age-related cognitive and motor declines. To better understand underlying mechanisms, we investigated the connection between markers of biological brain aging based on magnetic resonance imaging (MRI), cognitive and motor performance, as well as modifiable vascular risk factors, using a large-scale neuroimaging analysis in 40,579 individuals of the population-based UK Biobank and Hamburg City Health Study. Employing partial least squares correlation analysis (PLS), we investigated multivariate associative effects between three imaging markers of biological brain aging - relative brain age, white matter hyperintensities of presumed vascular origin, and peak-width of skeletonized mean diffusivity - and multi-domain cognitive test performances and motor test results. The PLS identified a latent dimension linking higher markers of biological brain aging to poorer cognitive and motor performances, accounting for 94.7% of shared variance. Furthermore, a mediation analysis revealed that biological brain aging mediated the relationship of vascular risk factors - including hypertension, glucose, obesity, and smoking - to cognitive and motor function. These results were replicable in both cohorts. By integrating multi-domain data with a comprehensive methodological approach, our study contributes evidence of a direct association between vascular health, biological brain aging, and functional cognitive as well as motor performance, emphasizing the need for early and targeted preventive strategies to maintain cognitive and motor independence in aging populations., Competing Interests: 6Competing interests JG has received speaker fees from Lundbeck, Janssen-Cilag, Lilly, Otsuka and Boehringer outside the submitted work. JF reported receiving personal fees from Acandis, Cerenovus, Microvention, Medtronic, Phenox, and Penumbra; receiving grants from Stryker and Route 92; being managing director of eppdata; and owning shares in Tegus and Vastrax; all outside the submitted work. GT has received fees as consultant or lecturer from Acandis, Alexion, Amarin, Bayer, Boehringer Ingelheim, BristolMyersSquibb/Pfizer, Daichi Sankyo, Portola, and Stryker outside the submitted work. The remaining authors declare no conflicts of interest.