期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2022
卷号：119
期号：5
DOI：10.1073/pnas.2120693119
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Accurate, nontargeted, comprehensive analysis of metabolites provides essential information about cutting-edge clinical questions (
1). Zheng et al. (
2) question the legitimacy of our recent discovery of dementia markers using whole-blood metabolomics (3).
First, they express concern about the sample size of our study (
n = 16) (
2). However, our findings (
3) do not conflict with other studies. Rather, they are well supported by other work. In addition to our study, a recent large-scale study of metabolomics (
n = 496) identified ergothioneine (ET) as a dementia marker (
4), while frail elderly patients, manifesting cognitive impairment, also display a decline in ET levels (
5). Moreover, the statistical analysis in our study was validated by a reviewer for this journal with expertise in statistics, during the review process. Thus, whole-blood metabolomics is a useful approach, since some dementia markers like ET are abundant in red blood cells.
Second, Zheng et al. (
2) note the age difference between test subjects with dementia and those who served as controls in our study (
3). It is possible that aging increases the risk of neurodegenerative diseases (
6). Previously, we reported individual differences in 126 blood metabolites between young (29 ± 4 y) and elderly people (81 ± 7 y) (
7). While 14 blood metabolites were listed as aging markers, most of the dementia markers, including ET, were not included in this list (
3). Indeed, an age-matched study for dementia markers drew conclusions similar to ours (
4).
Third, we agree that environmental factors, such as food and drugs, may affect metabolomic profiles. Patients with mild cognitive impairment (MCI) may progress to Alzheimer’s disease (
6), but, generally, MCI does not require drug administration. Metabolomics also identified ET as a marker for MCI (
5,
8), implying that drugs for dementia, like memantine, do not affect our conclusions. Accumulating data suggest that caffeine has a protective role on cognitive function through its stimulation of the central nervous system, consistent with our findings (
9,
10).
Usually, large-scale epidemiological surveys target specific metabolites, while our whole-blood metabolomics provide detailed, nontargeted, comprehensive analysis (
3). Thus, findings from the two approaches complement each other, which is why our nontargeted approach constitutes a significant, incremental advance in the field of disease metabolomics.
