Circulating metabolites are associated with brain atrophy and white matter hyperintensities

Abstract

Introduction Our aim was to study whether systemic metabolites are associated with magnetic resonance imaging (MRI) measures of brain and hippocampal atrophy and white matter hyperintensities (WMH). Methods We studied associations of 143 plasma‐based metabolites with MRI measures of brain and hippocampal atrophy and WMH in three independent cohorts (n = 3962). We meta‐analyzed the results of linear regression analyses to determine the association of metabolites with MRI measures. Results Higher glucose levels and lower levels of three small high density lipoprotein (HDL) particles were associated with brain atrophy. Higher glucose levels were associated with WMH. Discussion Glucose levels were associated with brain atrophy and WMH, and small HDL particle levels were associated with brain atrophy. Circulating metabolites may aid in developing future intervention trials.

Plasma metabolomic profiles of dementia: a prospective study of 110,655 participants in the UK Biobank

“…This association is further explained by recent evidence suggesting the utilization of ketone bodies in the brain largely relies on their plasma concentration [ 35 ] and transportation capacity across the BBB [ 36 ]. Our association with peripheral citrate is concordant with FA Leeuw et al whom observed higher levels of plasma citrate were associated with brain and hippocampal atrophy, and white matter hyperintensity, which are known neurological changes associated with AD and dementia [ 37 ]. Furthermore, these metabolic disturbances are replicated in animal AD model brains [ 33 , 38 , 39 ].…”

“…Strong negative correlations were observed between small high-density lipoproteins (HDL), its lipid constituents (including total lipids, cholesteryl esters, cholesterol, free cholesterol, and phospholipids) and incident dementia in the present analysis. Similar findings have been replicated by previous studies although an adequate explanation on these observations is yet to be fully realized [ 37 , 40 , 41 ]. Of note, Martinez et al recently showed small HDL was the only lipoprotein that could pass the BBB, which implies it plays a role in the balance and distribution of fats within the brain [ 42 ].…”

“…Of note, LDL-C is a conventional risk factor in cardiovascular and metabolic diseases, although its role in dementia has been historically conflicting [ 48 , 49 ]. Furthermore, the different roles of lipoprotein subclasses may be attributed to their ability to cross the BBB, which makes the lipid environment in the brain very different from the periphery [ 37 ]. Nonetheless, several hypotheses may explain our findings, including the presumed role of triglycerides for interfering with peripheral Aβ transportation and facilitating PUFA absorption [ 50 ].…”

Effects of Obesity, Blood Pressure, and Blood Metabolic Biomarkers on Grey Matter Brain Healthcare Quotient: A Large Cohort Study of a Magnetic Resonance Imaging Brain Screening System in Japan

“…A previous study of 789 older adults also reported no significant correlation between high HDL levels and brain volume [ 35 ]. Furthermore, Leeuw et al reported that LDL and HDL were not associated with brain volume in 3962 participants [ 36 ]. Conversely, Leeuw et al also reported that higher levels of small HDL in HDL subclasses were related to smaller brain volume [ 36 ].…”

“…Furthermore, Leeuw et al reported that LDL and HDL were not associated with brain volume in 3962 participants [ 36 ]. Conversely, Leeuw et al also reported that higher levels of small HDL in HDL subclasses were related to smaller brain volume [ 36 ]. The current knowledge on HDL subclasses is limited, although small HDL has been suggested to have more antioxidant and anti-inflammatory properties than lipid-rich large HDL [ 37 ].…”