Altered Bile Acid Metabolites in Mild Cognitive Impairment and Alzheimer’s Disease

MedicalResearch.com Interview with:

Kwangsik Nho, PhD Assistant Professor of Radiology & Imaging Sciences Indiana University School of Medicine Indianapolis, IN, 

Dr. Kwangsik Nho

Kwangsik Nho, PhD
Assistant Professor of Radiology & Imaging Sciences
Indiana University School of Medicine
Indianapolis, IN

MedicalResearch.com: What is the ADNI (Alzheimer’s Disease Neuroimaging Initiative)?

Response: The initial phase (ADNI-1) was launched in 2003 to test whether serial magnetic resonance imaging (MRI), position emission tomography (PET), other biological markers, and clinical and neuropsychological assessment could be combined to measure the progression of mild cognitive impairment (MCI) and early Alzheimer’s Disease (AD). ADNI-1 was extended to subsequent phases (ADNI-GO, ADNI-2, and ADNI-3) for follow-up for existing participants and additional new enrollments. To our knowledge, the ADNI cohort (370 cognitively normal older adults, 98 patients with significant memory concern, 284 early MCI, 505 late MCI, and 305 patients with AD) uniquely has multi-omics data sets including metabolomics and structural and functional neuroimaging data (MRI, PET) as well as rich clinical and fluid biomarker data on the same participants.

MedicalResearch.com: Why did you choose those methods and targets?

Response: Cholesterol is synthesized in liver and its clearance involves bile acid production by gut microbiome and human co-metabolism. Bile acids have major regulatory and signaling functions. Changes in microbial gut populations can profoundly alter bile acid profiles and signaling. Research in  Alzheimer’s Disease animal models suggests a role for the gut microbiome in the development of amyloid-β pathology. However, little work has been done in humans to link peripheral circulating metabolic changes in cholesterol to brain changes and cognitive functions in Alzheimer’s Disease including amyloid-β and tau accumulation, brain glucose metabolism, and structural atrophy. Studying peripheral metabolic influences on brain in health and disease is important. We focused on cholesterol metabolism and its clearance through bile acid production reactions that involve liver and gut microbiome enzymatic activities. 

MedicalResearch.com: What did you do?

Response: We measured serum levels of 15 bile acid metabolites and their 8 ratios from older adults with early stage AD or who were at risk for Alzheimer’s Disease from the ADNI cohort. We assessed the association of targeted bile acids with amyloid, tau, and neurodegeneration biomarkers for AD based on the recently proposed NIA-Alzheimer’s Association 2018 Research Framework using CSF biomarkers and neuroimaging biomarkers (brain atrophy (MRI), and brain glucose metabolism (FDG-PET)).

MedicalResearch.com: What did you find? 

Response: We found a link of bile acid profiles of the gut microbiome and liver function to AD-related structural (hippocampal volume measured from MRI scans) and functional neuroimaging (brain glucose metabolism measured from FDG PET scans) biomarkers as well as biomarkers of amyloid-β and tau burden (CSF Aβ1-42, CSF p-tau, CSF t-tau)  after adjusting for multiple testing using the false discovery rate (FDR) (corrected p<0.05):

  • Lower serum concentrations of primary bile acids synthesized in the liver from cholesterol were significantly associated with worst cognitive performance, larger brain structural atrophy, and decreased brain glucose metabolism.
  • Higher serum concentrations of secondary bile acids produced in the gut by bacteria were significantly associated with increased tau accumulation in brain, larger brain structural atrophy, and decreased brain glucose metabolism.
  • Higher serum concentrations of ratios of bacterially produced conjugated secondary bile acids to primary bile acids were significantly associated with increased amyloid-β accumulation, larger brain structural atrophy, and decreased brain glucose metabolism.

MedicalResearch.com: What of that was new to you? 

Response: This is the first study to demonstrate that serum-based altered (higher or lower) bile acid levels are associated with the amyloid, tau, and neurodegeneration biomarkers of AD pathophysiology, providing further support for a role of bile acid pathways in AD pathophysiology. Circulating bile acids may play a role in normal chemical communication between the gut/liver and the brain (“Gut-Liver-Brain Axis”). 

MedicalResearch.com: What do you think the implications are for Alzheimer’s diagnosis, treatment and prevention?

Response: Bile acid signaling pathways may lead to the identification of metabolites that are protective against Alzheimer’s Disease and could foster novel therapeutic strategies, if a causal role can be demonstrated in future studies. New therapies based on modulation of gut microbiome with diet, drugs, or probiotics could emerge as new approaches to the treatment of Alzheimer’s Disease. 

MedicalResearch.com: What are next steps for research?

Response: Although the Gut-Brain Axis may be dysregulated in AD, a longitudinal study covering pre-symptomatic stages, prospective clinical observations, and validation in AD animal model systems are needed to assess causality and the specific mechanisms underlying this association. 

Funding: This study was carried out in the Alzheimer Disease Metabolomics Consortium (ADMC) funded by NIA through AMP-AD and M2OVE-AD consortia as well as with additional funding by NIH-NLM.

Citation: 

Altered Bile Acid Profile in Mild Cognitive Impairment and Alzheimer’s Disease: Relationship to Neuroimaging and CSF Biomarkers

Kwangsik Nho, Alexandra Kueider-Paisley, Siamak MahmoudianDehkord, Matthias Arnold, Shannon L. Risacher, Gregory Louie, Colette Blach, Rebecca Baillie, Xianlin Han, Gabi Kastenmueller, Wei Jia, Guoxiang Xie, Shahzad Ahmad, Thomas Hankemeier, Cornelia M. van Duijn, John Q. Trojanowski, Leslie M. Shaw, Michael W. Weiner, P. Murali Doraiswamy, Andrew J. Saykin, Rima Kaddurah-Daouk, Alzheimers Disease Neuroimaging Initiative, Alzheimer Disease Metabolomics Consortium

doi: https://doi.org/10.1101/28414 

Aug 9, 2018 @ 12:06 am 

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