Abnormal Serum Bilirubin/Albumin Concentrations in Dementia Patients With Aβ Deposition and the Benefit of Intravenous Albumin Infusion for Alzheimer's Disease Treatment.

Qi Peng,Weiru Zhang,Weimin Lao,Xingxiao Huang,Yuning Liao,Yuping Ning,Hong Chen,Wanyuan Liang,Chang-E Zhang,Cong Ouyang,Caijun Li,Zhangying Wu,Xinru Chen,Xiaomei Zhong,Naikeng Mai,Xuejun Wang,Ben Chen,Jinbao Liu,Min Zhang

doi:10.3389/fnins.2020.00859

Abstract

BackgroundOur previous study in animal models revealed that bilirubin could induce Aβ formation and deposition. Bilirubin may be important in neurodegenerative dementia with Aβ deposition. Hence, lowering the concentration of the free bilirubin capable of crossing the blood brain–barrier may benefit the treatment of Alzheimer’s disease (AD).ObjectivesThe objectives of this study were to examine the change in the serum bilirubin and albumin concentrations of dementia patients with Aβ deposition, and to determine the effects of intravenous administration of albumin in the treatment of AD.MethodsBilirubin and albumin concentrations in dementia patients with Aβ deposition were examined. Cell viability and apoptosis were determined in dopaminergic neuron-like cells MN9D treated with bilirubin in the presence of diverse concentrations of serum. Human albumin at a dose of 10 g every 2 weeks for 24 weeks was administered intravenously to AD patients to examine the effect of albumin on AD symptoms.ResultsSignificantly higher indirect bilirubin (IBIL) concentrations, lower albumin concentrations, and higher ratio of IBIL to albumin (IBIL/ALB) were observed in dementia patients with Aβ deposition, including AD, dementia with Lewy bodies, and general paresis of insane. In vitro assays showed that bilirubin-induced injury in cultured dopaminergic neuron-like cells negatively depends on the concentration of serum in the culture medium. General linear model with repeated measures analysis indicated a main effect of group on the change in albumin concentrations and Alzheimer’s Disease Cooperative Study Activities of Daily Living Inventory scale (ADCS-ADL) scores, and the main effect of time and group, and group-by-time interaction on the change of Clinical Dementia Rating Scale–Sum of Boxes (CDR-SB) scores. Analysis of the combined data of the entire 28 weeks of assessment period using the area under curve convincingly showed significantly improvements in the change of albumin concentrations, ADCS-ADL scores, and CDR-SB scores.ConclusionIBIL and the IBIL/ALB ratio are significantly higher in dementia patients with Aβ deposition, and intravenous administration of albumin is beneficial to AD treatment.Trial RegistrationThe intervention study was registered at http://www.chictr.org.cn (ChiCTR-IOR-17011539). Date of registration: June 1, 2017.

Highlights

Around the world, 50 million people are living with dementia, and one new case is expected to develop every 3 s
We found that serum indirect bilirubin (IBIL) values and the IBIL/ALB were significantly higher in the two most common forms of neurodegenerative dementia (AD and dementia with Lewy bodies (DLB)), as well as infectious dementia [GPI, which has been proven to be associated with Aβ deposits (Miklossy, 2008)]
The correlations of serum bilirubin concentrations with Mini-Mental State Examination (MMSE) scores in dementia patients with Aβ deposition revealed by our study indicate that the IBIL concentrations and the ratios of IBIL/ALB may have a negative impact on the cognitive function

Summary

Introduction

50 million people are living with dementia, and one new case is expected to develop every 3 s. Neurodegenerative diseases are the major cause of cognitive impairments and can lead to dementia. Our previous study has demonstrated that the neurotoxicity of bilirubin is associated with its proteasome inhibition properties. Relevant elevation of bilirubin concentrations can act as an endogenous proteasome inhibitor and inhibit UPS-mediated protein degradation, which may affect the degradation of Aβ and lead to its abnormal accumulation (Hong et al, 2014). Our prior study using primary hippocampal neurons and animal models has shown that bilirubin induces Aβ deposition and formation, and tau hyperphosphorylation, by activating GSK-3β, CDK5, and JNK, increasing the expression of amyloid-β protein precursor (AβPP) γ-secretase PS2, and decreasing the expression of α-secretase ADAM17 (Chen et al, 2020). Our previous study in animal models revealed that bilirubin could induce Aβ formation and deposition. Bilirubin may be important in neurodegenerative dementia with Aβ deposition. Lowering the concentration of the free bilirubin capable of crossing the blood brain–barrier may benefit the treatment of Alzheimer’s disease (AD)

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Conclusion