Association of liver fibrosis with cognitive test performance and brain imaging parameters in the UK Biobank study

Parikh, Neal S; Kamel, Hooman; Zhang, Cenai; Gupta, Ajay; Cohen, David E.; Leon, Mony J. de; Gottesman, Rebecca F.; Iadecola, Costantino

doi:10.1002/alz.12795

Cited by 11 publications

(27 citation statements)

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“…Yet, in contrast to our results, the prior UK Biobank study also demonstrated an association of fibrosis with lower hippocampal volume [12]. The latter discrepancy may stem from differences in ascertainment of liver fibrosis, which was done indirectly through serum-based markers in the former study.…”

Section: Of 11contrasting

confidence: 99%

“…In turn, patients with NASH are prone to disease progression to various stages of fibrosis, as well as cirrhosis and eventually hepatocellular carcinoma [9]. Mounting evidence demonstrates an association of liver fibrosis with an increased risk of stroke [10], poor cognitive function [11][12][13], and higher rates of incident dementia [14]. Furthermore, liver fibrosis was observed to be associated with lower total brain and hippocampal volumes in a large sample of the UK Biobank study [12].…”

Section: Introductionmentioning

confidence: 99%

“…Mounting evidence demonstrates an association of liver fibrosis with an increased risk of stroke [10], poor cognitive function [11][12][13], and higher rates of incident dementia [14]. Furthermore, liver fibrosis was observed to be associated with lower total brain and hippocampal volumes in a large sample of the UK Biobank study [12]. Nevertheless, despite being cheap, noninvasive, and highly accessible [15], the use of blood-based algorithms for detecting liver fibrosis only limits the detection of liver fibrosis, and could be improved by imaging measures such as ultrasound and elastography of the liver to increase diagnosis accuracy and robustness of previous findings [15].…”

Section: Introductionmentioning

confidence: 99%

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Nonalcoholic fatty liver disease, liver fibrosis, and structural brain imaging: The Cross‐Cohort Collaboration

Weinstein,

O'Donnell,

Frenzel

et al. 2023

Euro J of Neurology

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Background and purposePrior studies reported conflicting findings regarding the association of nonalcoholic fatty liver disease (NAFLD) and liver fibrosis with measures of brain health. We examined whether NAFLD and liver fibrosis are associated with structural brain imaging measures in middle‐ and old‐age adults.MethodsIn this cross‐sectional study among dementia‐ and stroke‐free individuals, data were pooled from the Offspring and Third Generation cohorts of the Framingham Heart Study (FHS), the Rotterdam Study (RS), and the Study of Health in Pomerania. NAFLD was assessed through abdominal imaging. Transient hepatic elastography (FibroScan) was used to assess liver fibrosis in FHS and RS. Linear regression models were used to explore the relation of NAFLD and liver fibrosis with brain volumes, including total brain, gray matter, hippocampus, and white matter hyperintensities, adjusting for potential confounders. Results were combined using fixed effects meta‐analysis.ResultsIn total, 5660 and 3022 individuals were included for NAFLD and liver fibrosis analyses, respectively. NAFLD was associated with smaller volumes of total brain (β = −3.5, 95% confidence interval [CI] = −5.4 to −1.7), total gray matter (β = −1.9, 95% CI = −3.4 to −0.3), and total cortical gray matter (β = −1.9, 95% CI = −3.7 to −0.01). In addition, liver fibrosis (defined as liver stiffness measure ≥8.2 kPa) was related to smaller total brain volumes (β = −7.3, 95% CI = −11.1 to −3.5). Heterogeneity between studies was low.ConclusionsNAFLD and liver fibrosis may be directly related to brain aging. Larger and prospective studies are warranted to validate these findings and identify liver‐related preventive strategies for neurodegeneration.

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Section: Of 11contrasting

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Nonalcoholic fatty liver disease, liver fibrosis, and structural brain imaging: The Cross‐Cohort Collaboration

Weinstein,

O'Donnell,

Frenzel

et al. 2023

Euro J of Neurology

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“…2012). In a newly published cohort research employing the UK Biobank, fibrosis and cirrhosis of the liver were strongly linked to an elevated risk of incident dementia, cognitive impairment, and cognitive‐related brain structures (Parikh, Kamel, Zhang, Gupta, et al., 2022; Parikh, Kamel, Zhang, Kumar, et al., 2022). Liver fibrosis is believed to lead to liver cirrhosis which, in turn, leads to hepatic encephalopathy, the pathophysiology of which involves astrocyte and neuronal modifications caused by inflammation, dietary and metabolic variables, ammonia build‐up, and neurosteroid‐induced GABAergic system activation, leading to the pathological changes that are observed in AD (Butterworth, 2019; Rose et al., 2020).…”

Section: Discussionmentioning

confidence: 99%

“…Additionally, Parikh et al. proposed that liver fibrosis is associated with a higher risk of dementia, cognitive impairment, and cognitive‐related abnormal brain structure (Parikh, Kamel, Zhang, Gupta, et al., 2022; Parikh, Kamel, Zhang, Kumar, et al., 2022). Although the results of these studies have provided some evidence of the potential relationship between liver function and cognitive function, the underlying link remains unclear.…”

Section: Introductionmentioning

confidence: 99%

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

Gao,

Ou,

Wang

et al. 2023

Journal of Neurochemistry

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The relationship between liver dysfunction and dementia has been researched extensively but remains poorly understood. In this study, we investigate the longitudinal and cross‐sectional associations between liver function and liver diseases and risk of incident dementia, impaired cognition, and brain structure abnormalities using Cox proportion hazard model and linear regression model. 431 699 participants with a mean of 8.65 (standard deviation [SD] 2.61) years of follow‐up were included from the UK Biobank; 5542 all‐cause dementia (ACD), 2427 Alzheimer's disease (AD), and 1282 vascular dementia (VaD) cases were documented. We observed that per SD decreases in alanine transaminase (ALT; hazard ratio [HR], 0.917; PFDR <0.001) and per SD increases in aspartate aminotransferase (AST; HR, 1.048; PFDR = 0.010), AST to ALT ratio (HR, 1.195; PFDR <0.001), gamma‐glutamyl transpeptidase (GGT; HR, 1.066; PFDR <0.001), alcoholic liver disease (ALD; HR, 2.872; PFDR <0.001), and fibrosis and cirrhosis of liver (HR, 2.285; PFDR = 0.002), being significantly associated with a higher risk of incident ACD. Restricted cubic spline models identified a strong U‐shaped association between Alb and AST and incident ACD (Pnonlinear <0.05). Worse cognition was positively correlated with AST, AST to ALT ratio, direct bilirubin (DBil), and GGT; negatively correlated with ALT, Alb, and total bilirubin (TBil); and ALD and fibrosis and cirrhosis of liver (PFDR <0.05). Moreover, changes in ALT, GGT, AST to ALT ratio, and ALD were significantly associated with altered cortical and subcortical regions, including hippocampus, amygdala, thalamus, pallidum, and fusiform (PFDR <0.05). In sensitivity analysis, metabolic dysfunction‐associated steatotic liver disease (MASLD) was associated with the risk of ACD and brain subcortical changes. Our findings provide substantial evidence that liver dysfunction may be an important factor for incident dementia. Early intervention in the unhealthy liver may help prevent cognitive impairment and dementia incidence.image

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Liver integrity and the risk of Alzheimer's disease and related dementias

Lu,

Pike,

Hoogeveen

et al. 2023

Alzheimer's & Dementia

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INTRODUCTIONWe examined midlife (1990–1992, mean age 57) and late‐life (2011–2013, mean age 75) nonalcoholic fatty liver disease (NAFLD) and aminotransferase with incident dementia risk through 2019 in the Atherosclerosis Risk in Communities (ARIC) Study.METHODSWe characterized NAFLD using the fatty liver index and fibrosis‐4, and we categorized aminotransferase using the optimal equal‐hazard ratio (HR) approach. We estimated HRs for incident dementia ascertained from multiple data sources.RESULTSAdjusted for demographics, alcohol consumption, and kidney function, individuals with low, intermediate, and high liver fibrosis in midlife (HRs: 1.45, 1.40, and 2.25, respectively), but not at older age, had higher dementia risks than individuals without fatty liver. A U‐shaped association was observed for alanine aminotransferase with dementia risk, which was more pronounced in late‐life assessment.DISCUSSIONOur findings highlight dementia burden in high‐prevalent NAFLD and the important feature of late‐life aminotransaminase as a surrogate biomarker linking liver hypometabolism to dementia.Highlights Although evidence of liver involvement in dementia development has been documented in animal studies, the evidence in humans is limited. Midlife NAFLD raised dementia risk proportionate to severity. Late‐life NAFLD was not associated with a high risk of dementia. Low alanine aminotransferase was associated with an elevated dementia risk, especially when measured in late life.

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Association of liver fibrosis with cognitive test performance and brain imaging parameters in the UK Biobank study

Cited by 11 publications

References 50 publications

Nonalcoholic fatty liver disease, liver fibrosis, and structural brain imaging: The Cross‐Cohort Collaboration

Nonalcoholic fatty liver disease, liver fibrosis, and structural brain imaging: The Cross‐Cohort Collaboration

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

Liver integrity and the risk of Alzheimer's disease and related dementias

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