Barbara B. Bendlin, PhD – Slide of the Week

Bendlin Slide of the Week

Title: The gut microbiota-derived metabolite trimethylamine N-oxide is elevated in Alzheimer’s disease

Legend: Trimethylamine N-oxide (TMAO) is a product of gut microbial metabolism of choline and carnitine (resulting in production of TMA which is them converted to TMAO by liver) and elevated plasma levels of TMAO have been associated with increased risk for future heart attack, stroke and all cause mortality. In this study, we examined TMAO levels in cerebrospinal fluid (CSF) collected from individuals who participated in Alzheimer’s disease-related studies. We found that TMAO levels in CSF are elevated among individuals with Alzheimer’s disease (AD) dementia, as well as individuals with mild cognitive impairment (MCI), compared to control (left panel). CSF levels of TMAO were also associated with neuropathology, as indexed by CSF levels of p-tau, t-tau, neurofilament light chain (NFL), and the ratio of p-tau/Aβ42. TMAO was not significantly associated with CSF Aβ42/Aβ40 or neurogranin (right panel).  Additional studies are needed to determine whether TMAO is directly linked to the development of brain pathology and cognitive decline, or incidentally elevated due to alterations in gut microbial composition in the context of AD. Further, the extent to which elevated TMAO levels may contribute to cerebrovascular disease in this population is an ongoing area of study.

Citation: Vogt NM, Romano KA, Darst BF, Engelman CD, Johnson SC, Carlsson CM, Asthana S, Blennow K, Zetterberg H, Bendlin BB, Rey FE. (2018). The gut microbiota-derived metabolite trimethylamine N-oxide is elevated in Alzheimer’s disease. Alzheimers Research & Therapy, 10(1):124. doi: 10.1186/s13195-018-0451-2.

Abstract: Background – Trimethylamine N-oxide (TMAO), a small molecule produced by the metaorganismal metabolism of dietary choline, has been implicated in human disease pathogenesis, including known risk factors for Alzheimer’s disease (AD), such as metabolic, cardiovascular, and cerebrovascular disease. Methods – In this study, we tested whether TMAO is linked to AD by examining TMAO levels in cerebrospinal fluid (CSF) collected from a large sample (n = 410) of individuals with Alzheimer’s clinical syndrome (n = 40), individuals with mild cognitive impairment (MCI) (n = 35), and cognitively-unimpaired individuals (n = 335). Linear regression analyses were used to determine differences in CSF TMAO between groups (controlling for age, sex, and APOE ε4 genotype), as well as to determine relationships between CSF TMAO and CSF biomarkers of AD (phosphorylated tau and beta-amyloid) and neuronal degeneration (total tau, neurogranin, and neurofilament light chain protein). Results – CSF TMAO is higher in individuals with MCI and AD dementia compared to cognitively-unimpaired individuals, and elevated CSF TMAO is associated with biomarkers of AD pathology (phosphorylated tau and phosphorylated tau/Aβ42) and neuronal degeneration (total tau and neurofilament light chain protein). Conclusions – These findings provide additional insight into gut microbial involvement in AD and add to the growing understanding of the gut-brain axis.

About the Lab: Bendlin’s lab focuses on brain structure and function in middle and late age, especially in people with increased risk of developing AD due to parental family history, genotype and vascular risk factors. Understanding early brain changes in people who may go on to develop AD is expected to lead to earlier diagnosis, prevention, and the development of new therapies for AD. Her current projects use MRI as a tool to understand the effect of risk factors (parental family history, genotype, metabolic syndrome) on brain blood flow and structure. Additionally, she is funded to examine the relationship between cerebrospinal fluid biomarkers and brain structure to learn more about early mechanisms of brain damage in AD.

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