Association Between Methylmalonic Acid and Cognition: A Systematic Review and Meta-Analysis

Abstract

BackgroundMethylmalonic acid (MMA) is an intermediate metabolite of human body. The content of MMA in the blood of healthy people is very low, and its concentration will increase in some diseases and elderly people. Recent studies have shown that MMA has a variety of biological functions. The correlation between MMA and cognition, one of the important functions of the nervous system, is still uncertain.ObjectiveMeta-analyses were performed to assess whether elevated MMA was associated with the risk of cognitive decline.Materials and MethodsCross-sectional studies, randomized controlled studies, and case-control studies on the relationship between MMA and cognition were obtained by searching PubMed, Web of Science, EMBASE, ProQuest, WANFANG MED ONLINE, China National Knowledge Infrastructure (CNKI) and Chongqing VIP until May 2022. Two researchers independently selected studies according to inclusion and exclusion criteria, evaluated study quality and extracted data. Meta-analyses were performed using Review Manager 5.4 software. The sensitivity analysis of meta-analysis was performed by One by one exclusion method.ResultsA total of 11 studies were included, including six cross-sectional studies, two randomized controlled studies, and three case-control studies, with a sample of 16,533 subjects. Meta-analysis showed that there was no significant difference in cognitive level between high-level MMA subjects and low-level MMA subjects in the general population [SMD = −2.19, 95% CI (−4.76 ∼ 0.38), Z = 1.67, P = 0.09]. In the population supplemented with VitB12, the increase of MMA level caused by VitB12 supplementation was not related to the change of cognition [SMD = 0.32, 95% CI (−0.19 ∼ 0.84) z = 1.22, P = 0.22]. There was also no significant difference in MMA levels between patients with dementia and the control group [WMD = 20.89, 95% CI (−5.13 ∼ 46.92), z = 1.57, P = 0.12].ConclusionIn the general population, whether VitB12 is supplemented or not, there is no correlation between the increase of MMA level and the decrease of cognitive level. In dementia diseases, the level of MMA did not change significantly. High levels of MMA may not be a risk factor for cognitive impairment. The exact relationship between MMA and cognition needs further research.Systematic Review Registration[https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021266310], identifier [CRD42021266310].

Correlations of Blood and Brain NMR Metabolomics with Alzheimer’s Disease Mouse Models

“…Moreover, we found an increase in propionate (which has been associated with an increased risk of cognitive decline in human subjects [35]) in both brain tissue and blood plasma, complementing results from prior studies using saliva samples [36]. MMA and propionic acidemia, characterized by increased concentrations of free MMA and propionate, can hinder mitochondrial function by disrupting Krebs Cycle and electron transport chain, producing reactive oxygen species (ROS) that lead to neurodegeneration and AD-related pathophysiology [37][38][39].…”

Commentary: Association between methylmalonic acid and cognition—A systematic review and meta-analysis

“…We have meticulously read the article "Association Between Methylmalonic Acid and Cognition: A Systematic Review and Meta-Analysis" by Wang et al, published in your esteemed journal (1). The objective of the study was fascinating as the authors tried to explore the correlation between the elevated levels of methylmalonic acid (MMA) and decline in cognition, which is an untouched area in research.…”