Does thiamine protect the brain from iron overload and alcohol‐related dementia?

Listabarth, Stephan; König, Daniel; Vyssoki, Benjamin; Hametner, Simon

doi:10.1002/alz.12146

Cited by 18 publications

(8 citation statements)

References 51 publications

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“…IREB2 is a gene encoding iron regulatory protein 2, which is an RNA-binding protein that is involved in the regulation of cellular iron metabolism [ https://www.genecards.org/cgi-bin/carddisp.pl?gene=IREB2 ]. Iron overload in the brain has previously been associated with cognitive decline in AUD [ 38 ]. Neurodegeneration has been reported in two subjects with bi-allelic loss of function variants in IREB2 [ 39 , 40 ].…”

Section: Discussionmentioning

confidence: 99%

Epigenome-wide association study of alcohol use disorder in five brain regions

Zillich

Frank

Streit

et al. 2021

Neuropsychopharmacol.

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Alcohol use disorder (AUD) is closely linked to the brain regions forming the neurocircuitry of addiction. Postmortem human brain tissue enables the direct study of the molecular pathomechanisms of AUD. This study aims to identify these mechanisms by examining differential DNA-methylation between cases with severe AUD (n = 53) and controls (n = 58) using a brain-region-specific approach, in which sample sizes ranged between 46 and 94. Samples of the anterior cingulate cortex (ACC), Brodmann Area 9 (BA9), caudate nucleus (CN), ventral striatum (VS), and putamen (PUT) were investigated. DNA-methylation levels were determined using the Illumina HumanMethylationEPIC Beadchip. Epigenome-wide association analyses were carried out to identify differentially methylated CpG-sites and regions between cases and controls in each brain region. Weighted correlation network analysis (WGCNA), gene-set, and GWAS-enrichment analyses were performed. Two differentially methylated CpG-sites were associated with AUD in the CN, and 18 in VS (q < 0.05). No epigenome-wide significant CpG-sites were found in BA9, ACC, or PUT. Differentially methylated regions associated with AUD case-/control status (q < 0.05) were found in the CN (n = 6), VS (n = 18), and ACC (n = 1). In the VS, the WGCNA-module showing the strongest association with AUD was enriched for immune-related pathways. This study is the first to analyze methylation differences between AUD cases and controls in multiple brain regions and consists of the largest sample to date. Several novel CpG-sites and regions implicated in AUD were identified, providing a first basis to explore epigenetic correlates of AUD.

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Section: Discussionmentioning

confidence: 99%

Epigenome-wide association study of alcohol use disorder in five brain regions

Zillich

Frank

Streit

et al. 2021

Neuropsychopharmacol.

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“…were not observed at lower intakes (SFigure 1). Levels of drinking necessary to observe higher susceptibility values differed according to region (SFigures [2][3][4][5][6].…”

Section: Associations With Brain Ironmentioning

confidence: 99%

“…One largely neglected possibility is that iron overload contributes to alcohol-related neurodegeneration [4, 5]. Whilst neurological sequelae of inherited iron overload disorders have long been recognised [6], higher brain iron has now been implicated in the pathophysiology of Alzheimer’s and Parkinson’s diseases [7, 8].…”

Section: Introductionmentioning

confidence: 99%

Impact of moderate alcohol consumption on brain iron and cognition: observational and genetic analyses

Topiwala

Wang

Ebmeier

et al. 2022

Preprint

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Brain iron deposition has been linked to several neurodegenerative conditions and reported in alcohol dependence. Whether iron accumulation occurs in moderate drinkers is unknown. Our objectives were to investigate causal relationships between alcohol consumption and brain iron levels and to examine whether higher brain iron represents a potential pathway to alcohol-related cognitive deficits. Multi-organ susceptibility-weighted magnetic resonance imaging was used to ascertain iron content of brain (quantitative susceptibility mapping (QSM) and T2*) and liver tissues (T2*), a marker of systemic iron. Observational associations between brain iron markers and self-reported alcohol consumption (n=22,254 UK Biobank participants) were compared with associations with genetically-predicted alcohol intake from two-sample Mendelian randomization (MR). Potential pathways to alcohol-related iron brain accumulation through elevated systemic iron stores (liver) were explored in causal mediation analysis. Cognition was assessed at the time of scan and in online follow-up. Alcohol consumption was associated with markers of higher iron in putamen (β=0.09 standard deviation (S.D.) [95% confidence interval 0.07 to 0.10]), caudate (β=0.06 [0.04 to 0.07]) and substantia nigra (β=0.04 [0.02 to 0.05]), and lower iron in the thalami (β= -0.05 [-0.06 to -0.03]). Quintile-based analyses found these effects in those consuming >7 units (56g) alcohol weekly. MR analyses provided some evidence these relationships are causal. A 1 S.D. higher genetically-predicted number of alcoholic drinks weekly associated with 0.25 [0.01 to 0.49] S.D. higher putamen susceptibility and 0.28 [0.05 to 0.50] S.D. higher hippocampus susceptibility. Genetically-predicted alcohol use disorder was causally related to higher putamen susceptibility (0.18 [0.001 to 0.35] S.D.), serum iron (0.12 [0.05 to 0.19] S.D.) and transferrin saturation (0.11[0.03 to 0.19] S.D.). Elevated liver iron was observed at just >11 units (88g) alcohol weekly (0.03 mg/g [0.01-0.05] higher c.f. <7 units (56g) weekly). Systemic iron levels partially mediated associations of alcohol intake with brain iron accumulation (proportion mediated: 32% [22 to 49]). Markers of higher basal ganglia iron were associated with accelerated age-related decline in executive function and fluid intelligence, and slower reaction times. This study represents the largest investigation of moderate alcohol consumption and iron homeostasis to date. Even low levels of alcohol consumption were associated with iron accumulation in the brain, suggesting a potential mechanism for alcohol-related cognitive decline.

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“…Fatigue, weakness, depressed mood, and retardation of cognitive development in children can result from the altered metabolism of Fe [ 38 , 39 , 40 , 41 ]. The crucial proteins related to Fe metabolism are Hep, transferrin (Tf), and ferroportin-1 (Fpn-1) [ 42 ].…”

Section: Iron Metabolismmentioning

confidence: 99%

Iron Deficiency in Obesity and after Bariatric Surgery

et al. 2021

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Iron deficiency (ID) is particularly frequent in obese patients due to increased circulating levels of acute-phase reactant hepcidin and adiposity-associated inflammation. Inflammation in obese subjects is closely related to ID. It induces reduced iron absorption correlated to the inhibition of duodenal ferroportin expression, parallel to the increased concentrations of hepcidin. Obese subjects often get decreased inflammatory response after bariatric surgery, accompanied by decreased serum hepcidin and therefore improved iron absorption. Bariatric surgery can induce the mitigation or resolution of obesity-associated complications, such as hypertension, insulin resistance, diabetes mellitus, and hyperlipidemia, adjusting many parameters in the metabolism. However, gastric bypass surgery and sleeve gastrectomy can induce malabsorption and may accentuate ID. The present review explores the burden and characteristics of ID and anemia in obese patients after bariatric surgery, accounting for gastric bypass technique (Roux-en-Y gastric bypass—RYGB) and sleeve gastrectomy (SG). After bariatric surgery, obese subjects’ iron status should be monitored, and they should be motivated to use adequate and recommended iron supplementation.

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Does thiamine protect the brain from iron overload and alcohol‐related dementia?

Cited by 18 publications

References 51 publications

Epigenome-wide association study of alcohol use disorder in five brain regions

Epigenome-wide association study of alcohol use disorder in five brain regions

Impact of moderate alcohol consumption on brain iron and cognition: observational and genetic analyses

Iron Deficiency in Obesity and after Bariatric Surgery

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