Associations of liver dysfunction with incident dementia, cognition, and brain structure: A prospective cohort study of 431 699 adults

Gao, Pei‐Yang; Ou, Ya‐Nan; Wang, Hui‐Fu; Wang, Zhi‐Bo; Fu, Yan; He, Xiao‐Yu; Ma, Ya‐Hui; Feng, Jian‐Feng; Cheng, Wei; Tan, Lan; Yu, Jin‐Tai

doi:10.1111/jnc.15988

Cited by 8 publications

(1 citation statement)

References 53 publications

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“…However, no study so far demonstrated whether D3 modi es its function in the brain secondary to different diseases, as Alzheimer, or the metabolic dysfunction associated steatotic liver disease (MASLD). Remarkably, as in Alzheimer disease (AD), liver dysfunction is accompanied by cognitive loss (Gao et al, 2024).…”

Section: Introductionmentioning

confidence: 99%

Type 3 Deiodinase is Induced in Brain Of Two Models Leading to Cognitive Impairment

Dreher,

Oliveira,

Sindô¹

et al. 2024

Preprint

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Thyroid hormone is the regulator of brain cell maintenance, plasticity and energy production. The activation process of T4 into T3 depends on type 1 and 2 deiodinases, and type 3 (D3) inactivates T3. Several mechanisms, as oxidative stress, led by disease, imbalances D3 function. The response of D3 in the adult brain tissue in the context of different diseases is not defined. We evaluated D3 induction and its effects in the brain of two animal models. Methodology: To the metabolic-dysfunction associated steatotic liver disease (MASLD) model, male/adult Sprague Dawley rats (n=20) were assigned to control group (standard diet–2.93kcal/g) or high-fat-diet group (HFCD–4.3kcal/g). In the streptozotocin-induced Alzheimer's model (AD), adult Wistar rats (n=16) were allocated to the control group (5uL of citrate) or 5uL of streptozotocin. Sham animals were used as controls. Inflammation status, oxidative stress parameters, D3 expression and protein, as well as T3 controlled genes and endoplasmic stress and mitochondrial function were determined. Cerebral tissue from both groups had augmented carbonyl (P<0.001), reduced sulfhydryl and glutathione levels (P<0.001). D3 was induced (~30% in each group, P<0.0001) in both MASLD and AD groups trough ERK pathway, while genes controlled by T3 were diminished, suggesting diminished levels of T3 in the brain. Augmented endoplasmic reticulum stress and diminished mitochondrial biogenesis were observed in both models (P=0.001). The augmented T3 inactivation by D3 dysfunction in brain of both models results in a cascade of cell disruptions, most probably accelerating disease progression or worsening symptoms.

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Section: Introductionmentioning

confidence: 99%

Type 3 Deiodinase is Induced in Brain Of Two Models Leading to Cognitive Impairment

Dreher,

Oliveira,

Sindô¹

et al. 2024

Preprint

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Cognitive impairment in patients awaiting kidney and liver transplantation—A clinically relevant problem?

Golenia,

Olejnik,

Grusiecka‐Stańczyk

et al. 2024

Brain and Behavior

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IntroductionCognitive impairment (CI) is common in both end‐stage kidney disease (ESKD) and alcohol‐related liver cirrhosis. The aim of this study was to assess the prevalence and patterns of CI in patients awaiting kidney and liver transplantation, and to identify its determinants.MethodsIn this cross‐sectional, prospective study, 31 consecutive patients with ESKD and 31 consecutive patients with alcohol‐related liver cirrhosis, all currently on transplant waiting lists, were screened for cognitive decline using the Addenbrooke's Cognitive Examination. Medical history, demographics, and laboratory test results were also collected.ResultsThe prevalence of CI among patients with ESKD and alcohol‐related liver cirrhosis was 26% and 90%, respectively. In both groups, memory was the most affected cognitive domain, along with verbal fluency in patients with ESKD, and visuospatial abilities in patients with alcoholic cirrhosis. The most statistically significant increase in the prevalence of CI was found in patients with lower educational attainment, in both alcohol‐related liver cirrhosis and ESKD populations as well as in older patients with alcoholic cirrhosis. Furthermore, better cognitive functioning in ESKD patients was associated with higher levels of total lymphocyte count and alanine transaminase (ALT), and in alcohol‐related liver cirrhosis patients with higher levels of ALT and aspartate transaminase. A nonsignificant trend toward lower memory domain scores was also observed with increasing ammonia levels and increasing severity of liver disease (higher Child–Pugh scores). Finally, suboptimal performance on the screening test was correlated with the severity of liver disease as assessed by the Model for End‐Stage Liver Disease Sodium (MELD‐Na), but not at the statistically significant level.ConclusionsThe prevalence of CI, especially in patients with alcohol‐related liver cirrhosis, is high and can be a significant clinical problem, negatively affecting the transplantation process. Routine screening tests in this group would contribute to the implementation of appropriate management, such as rehabilitation program or psychosocial treatments and facilitate the provision of specialized health care.

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Liver enzyme and risk of vascular dementia: A univariable and multivariable Mendelian randomization of European descent

Chen,

Liang

et al. 2024

Neuroprotection

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BackgroundObservational studies have indicated a link between liver enzymes and dementia, but the causal relationship remains uncertain. We conducted a two‐sample Mendelian randomization (MR) study to investigate potential causal links between liver function markers (alanine aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase [ALP], and γ‐glutamyltransferase [GGT]) and various forms of dementia (all‐cause dementia, Alzheimer's disease [AD], vascular dementia [VaD], and frontotemporal dementia [FTD]).MethodsGenome‐wide association study (GWAS) data of liver enzyme levels with 517 single nucleotide polymorphisms from 315,572 individuals of European descent were considered as exposures. Additional GWAS data on dementia from the FinnGen consortium and the UK Biobank were used as outcomes. The causal relationship was evaluated using univariable MR (UVMR) and multivariable MR (MVMR) methods. UVMR approaches such as inverse variance weighting (IVW), MR‐Egger, weighted median, simple mode, and weighted mode were used, with IVW as primary. MVMR techniques, such as extended versions of IVW, MR‐Egger, and Q‐minimization methods, were used to assess causal effects. The robustness of the MR analysis findings was verified through heterogeneity, horizontal pleiotropy, and leave‐one‐out analyses.ResultsMVMR analysis demonstrated that a genetically determined one standard deviation rise in blood GGT levels was associated with an increased risk of VaD (IVW: odds ratio = 1.007, 95% confidence interval = 1.002–1.011, p = 0.010). These findings remained consistent after adjusting for confounding variables in MVMR analysis. Sensitivity analyses further supported the causal relationship. However, no significant links were observed between ALT, AST, ALP, and all‐cause dementia, VaD, AD, or FTD.ConclusionsOur study suggests clinical implications, demonstrating that high blood GGT concentrations are potential causal risk factors for VaD in European populations. Further research is needed to uncover the underlying biological mechanisms between GGT and VaD and validate the clinical relevance of early prevention and intervention strategies.

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Associations of liver dysfunction with incident dementia, cognition, and brain structure: A prospective cohort study of 431 699 adults

Cited by 8 publications

References 53 publications

Type 3 Deiodinase is Induced in Brain Of Two Models Leading to Cognitive Impairment

Type 3 Deiodinase is Induced in Brain Of Two Models Leading to Cognitive Impairment

Cognitive impairment in patients awaiting kidney and liver transplantation—A clinically relevant problem?

Liver enzyme and risk of vascular dementia: A univariable and multivariable Mendelian randomization of European descent

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