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To the best of our knowledge, this study represents the largest investigation of moderate alcohol consumption and iron homeostasis to date. Alcohol consumption above 7 units weekly associated with higher brain iron. Iron accumulation represents a potential mechanism for alcohol-related cognitive decline.
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Data Availability: Imaging and observational data underlying the results presented are available from the UK Biobank upon successful application ( -yourresearch/apply-for-access). Genetic summary statistics for serum iron measures are freely available ( ), as are GSCAN summary statistics ( ). Summary statistics for alcohol use disorder are available upon application through dfGaP at accession no. phs0016732.v3.p1 ( -bin/study.cgi study_id=phs001672.v3.p1).
Funding: AT is supported by a Wellcome Trust ( ) fellowship (216462/Z/19/Z). CW is funded, in part, by the China Scholarship Council (CSC, ). KPE is funded by the UK Medical Research Council ( , G1001354 & MR/K013351/1) and the European Commission ( , Horizon 2020 732592). CM is funded by the NIHR Oxford Biomedical Research Centre (IS-BRC-1215-20008) and the BHF Centre of Research Excellence, Oxford. JG, DL and HZ are supported by the US Department of Veterans Affairs ( , I01CX001849). SBu is supported by a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society ( , 204623/Z/16/Z). SBe was supported by the British Heart Foundation ( -professionals/information-for-researchers/what-we-fund, RG/16/4/32218) and the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014). MH is supported by the Wellcome Trust (206330/Z/17/Z) and NIHR Oxford Biomedical Research Centre (IS-BRC-1215-20008). SS is supported by a Wellcome Trust Collaborative Award 215573/Z/19/Z. KLM is supported by a Wellcome Trust Senior Research Fellowship (202788/Z/16/Z). TN is supported by the Li Ka Shing Centre for Health Information and Discovery, an NIH grant ( , TN: R01EB026859), the National Institute for Health Research Oxford Biomedical Research Centre (BRC-1215-20014), and a Wellcome Trust award (TN: 100309/Z/12/Z). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Participants were scanned as part of the UK Biobank (UKB) study [19], which recruited volunteers aged 40 to 69 years in 2006 to 2010. Invitations for imaging were sent to all participants. Interested individuals then underwent screening to assess if they were safe and able to tolerate imaging. To date, approximately 50,000 participants have brain scans analysed and approximately 15,000 have abdominal imaging. UKB received ethical approval from the Research Ethics Committee (reference 11/NW/0382), and all participants provided written informed consent. All participants with complete data were included (S1 Fig). No exclusions were made on the basis of dementia diagnosis as no participants with complete data had dementia at the time of imaging. As our study was conducted using existing resources to test an a priori hypothesis, we did not publish a prespecified analysis plan before conducting analyses between November 2021 and January 2022. Further analyses were subsequently performed in March 2022 in response to peer review where highlighted. This study is reported as per the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guideline, including guidelines specific for MR studies (S1 and S2 Checklists).
Alcohol intake was self-reported at study baseline through a touchscreen questionnaire. Participants identified themselves as either current, never, or previous drinkers. All groups were included if they had complete data on alcohol intake. For current drinkers, total weekly number of United Kingdom units (1 unit = approximately 8 g; a United States standard drink is 14 g) of alcohol consumed was calculated by summing across beverage types as previously described [20]. To directly compare associations with brain iron at different levels of alcohol intakes, weekly consumption was categorized into quintiles (and octiles for a sensitivity analysis) in current drinkers. The lowest quintile of drinkers was used as the reference category to avoid underestimating alcohol-related risks [21].
Participants underwent brain MRI at 3 imaging centres (Newcastle upon Tyne, Stockport, or Reading) with identical Siemens Skyra 3T scanners (software VD13) using a standard 32-channel head coil (release date 02.02.2021). Susceptibility-weighted MRI (swMRI) data were used for this study (3D GRE, TE1/TE2/TR = 9.4/20/27 ms, voxel size = 0.8 0.8 2.0 mm) as a measure sensitive to magnetic tissue constituents. Detailed image preprocessing and quality control pipelines are described elsewhere [22]. Brain iron content was ascertained using quantitative susceptibility mapping (QSM) and T2*, both derived from swMRI data. T2* reflects differences in tissue microstructure related to iron (sequestered to ferritin) and myelin and correlates with postmortem estimates of iron deposits in brain grey matter [23]. Susceptibility reflects the net (sequestered and non-sequestered) content of susceptibility-shifting sources like iron and myelin. Two distinct and complementary metrics of brain iron deposition were used, T2* and QSM, to produce image-derived phenotypes (IDPs). While these metrics are coupled, consistent findings across the 2 will provide greater evidence that iron levels are affected. Subject-specific masks for 14 subcortical regions were derived from the T1-weighted structural brain scan. We then calculated IDPs corresponding to the median T2* and χ values for each region. The 14 regions correspond to left and right of the 7 subcortical structure regions of interest obtained from the T1 image: putamen, caudate, hippocampus, amygdala, pallidum, thalamus, and accumbens. Two additional IDPs were calculated from QSM (left and right substantia nigra) that were not available for T2*. In brief, T2* values were calculated from magnitude data. T2*-induced signal decay was calculated from the 2 echo times. T2* images were spatially filtered to reduce noise and transformed into the T1 space (by linear registration). QSM depends on phase images, which were obtained from individual coil channels, combined, masked, and unwrapped. Magnetic susceptibility (χ) was calculated using a QSM pipeline including background field removal, dipole inversion, and CSF referencing as described elsewhere [10]. Median χ values (in parts per billion) across voxels within each region were calculated, resulting in 16 QSM IDPs.
To our knowledge, this is the largest study of moderate alcohol consumption and multiorgan iron accumulation. It is also the first study to use MR to investigate causality of alcohol on serum and brain iron.
We did not observe widespread associations between susceptibility or T2* and other cognitive tests or self-reported motor measures. Brain iron is likely to be an early marker of disease, and participants may have been examined too early in the process to detect clinical manifestations. Additionally, we are not likely to have captured the best phenotypes to assess basal ganglia function in the absence of objective motor measurements such as gait speed or a pegboard test. Self-reported walking speed may poorly approximate actual motor function. The cognitive tests were limited in scope and concerns have been raised about the reliability of the tests used [34]. Healthy selection biases in UKB are well described, and are likely magnified in the imaging subsample, but will equally bias the study towards null results [78]. Furthermore, associations in UKB seem to track with those observed in representative cohorts [79].
The timing and dosage of oral iron are also controversial. Most studies have focused on treatment from mid-pregnancy, at or before 20 weeks gestation. This accords with screening tests common to regular clinical practice in many countries. A randomized, double-blind study from Denmark examined doses of between 20 and 80 mg of oral iron daily in 427 pregnant women. A dose of 40 mg was sufficient to prevent ID in 90% of women (and IDA in at least 95%) both during pregnancy and postpartum.15 No difference in gastrointestinal side-effects was observed. In a more recent Australian study of anaemic pregnant patients, a similar dosage regimen showed an improved side-effect profile with no substantial difference in haemoglobin response compared with higher doses.111 Regular low dosage of oral iron would appear to benefit the majority of women, preventing ID and IDA and avoiding the potential problems of raising the [Hb] too high. Furthermore, the gastrointestinal side-effect profile would appear to be acceptable in most cases.
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