Serum and CSF Metabolites in Stroke-Free Patients Are Associated With Vascular Risk Factors and Cognitive Performance

Abstract

Background and purpose : The aggregation of vascular risk factors (VRFs) can aggravate cognitive impairment in stroke-free patients. Metabolites in serum and cerebrospinal fluid (CSF) may irreversibly reflect early functional deterioration. This study evaluated small-molecule metabolites (<1,000 Da) in the serum and CSF of patients with different degrees of cerebrovascular burden and investigated the correlation between metabolism and cognitive performance associated with VRFs. Methods : The subjects were divided into a low-risk group (10-year stroke risk ≤ 5%), a middle-risk group (10-year stroke risk >5% and <15%), and a high-risk group (10 years stroke risk ≥ 15%) according to the Framingham stroke risk profile (FSRP) score, which was used to quantify VRFs. We assess the cognitive function of the participants. We semiquantitatively quantified the small molecules using liquid chromatography–tandem mass spectrometry (LC-MS/MS). The correlation between the small molecules and cognitive function, along with VRFs, was investigated to identify key small molecules and possible underlying metabolic pathways. Results : When the FSRP scores increased, the cognitive performances of the subjects decreased, specifically the performance regarding the tasks of immediate memory, delayed recall, and executive function. Seven metabolites (2-aminobutyric acid, Asp Asp Ser, Asp Thr Arg, Ile Cys Arg, 1-methyluric acid, 3-tert-butyladipic acid, and 5α-dihydrotestosterone glucuronide) in serum and three metabolites [Asp His, 13-HOTrE(r), and 2,5-di-tert-Butylhydroquinone] in CSF were significantly increased, and one metabolite (arachidonoyl PAF C-16) in serum was significantly decreased in high-risk group subjects. Among these metabolites, 1-methyluric acid, 3-tert-butyladipic, acid and Ile Cys Arg in serum and 13-HOTrE(r), 2,5-di-tert-butylhydroquinone, and Asp His in CSF were found to be negatively related with cognitive performance in the high-risk group. Arachidonoyl PAF C-16 in serum was found to be associated with better cognitive performance. Caffeine metabolism and the tricarboxylic acid cycle (TCA cycle) were identified as key pathways. Conclusions : 1-Methyluric acid, 3-tert-butyladipic acid, arachidonoyl PAF C-16, and Ile Cys Arg in serum and 13-HOTrE(r), 2,5-di-tert-butylhydroquinone, and Asp His in CSF were identified as potential biomarkers of vascular cognitive impairment (VCI) at the early stage. Caffeine metabolism and the TCA cycle may play important roles in the pathophysiology of VRF-associated cognitive impairment.

LC‐MS‐based urine metabolomics analysis of chronic subdural hematoma for biomarker discovery

“…Our results indicated that 5‐alpha‐Dihydrotestosterone glucuronide in urine was potentially related to the recovery of CSDH patients. Actually, 5‐alpha‐Dihydrotestosterone glucuronide in serum has been identified as significant metabolites in stroke‐free patients with vascular risk factors and cognitive performance [52]. And the changes of it in plasma also had been showed in TBI patients correlated inversely with neurological score [53].…”

Transcriptomics and metabolomics analysis reveal the anti-oxidation and immune boosting effects of mulberry leaves in growing mutton sheep

“…Generally, the synthesis of oxylipins fluctuates with the changes of physiological or pathological states (33).13-HOTrE is derived from ALA via the COX enzymatic pathway. Studies have revealed that 13-HOTrE levels are significantly increased in some diseases (34,35), such as acute liver injury. Therefore, it is generally thought to be a proinflammatory factor.…”

Cerebrospinal fluid metabolite alterations in patients with different etiologies, diagnoses, and prognoses of disorders of consciousness

“…LC-MS has been widely applied in research on neurological diseases. Through LC-MS-based metabolomic analyses, alterations in amino acid, fatty acid, and energy metabolism after TBI have been found (Chitturi et al, 2018); the pathophysiology of vascular cognitive impairment was determined to be caffeine metabolism and the tricarboxylic acid cycle (Peng et al, 2020).…”

“…Improvements in liquid chromatography‐mass spectrometry (LC‐MS) have led to great advances in metabolomic analyses (Cui et al., 2018 ). The metabolite profile in cerebrospinal fluid (CSF) can serve as a direct indicator of biological process variations in the brains of patients with DoC when it is difficult to differentiate these processes based on patient clinical manifestations (Peng et al., 2020 ). LC‐MS has been widely applied in research on neurological diseases.…”

“…LC‐MS has been widely applied in research on neurological diseases. Through LC‒MS‐based metabolomic analyses, alterations in amino acid, fatty acid, and energy metabolism after TBI have been found (Chitturi et al., 2018 ); the pathophysiology of vascular cognitive impairment was determined to be caffeine metabolism and the tricarboxylic acid cycle (Peng et al., 2020 ). Abnormal metabolism associated with other neurological disorders, including ischemic stroke (Au, 2018 ), brain tumors (Pandey et al., 2017 ), and neurodegenerative diseases (Luan et al., 2019 ), has also been studied.…”