Metabolite differences in vascular dementia and control human brain tissue

Background Vascular dementia is the second most common cause of dementia worldwide and is characterized by cerebrovascular pathology that presents as an amnestic dementia syndrome like Alzheimer’s disease. The main neuropathological and clinical features for vascular dementia have been described elsewhere, but little is understood about the underlying metabolic processes that may contribute to vascular dementia. Here we measure the metabolites of control brains and brains with cerebrovascular pathology to understand how they differ. Method The global biochemical profiles of post‐mortem human brain tissue from the gray matter of Brodmann area 9 was determined using mass spectroscopy. Brain tissue from 52 subjects with cerebrovascular pathology and 46 controls were analyzed and metabolites were compared. Metabolites were quantified using global untargeted metabolomics (HD4) and compared between cohorts using Welch’s two‐sample t‐test and random forest to rank metabolites in order of importance for predicting cerebrovascular pathology presence in tissue. Result Many of the metabolites in the top 20 most important predictors for cerebrovascular pathology overlapped with metabolites deemed important in predicting Alzheimer’s disease, including memantine, sphingadienine, N‐acetylasparagine, N‐acetyl‐aspartyl‐glutamate (NAAG), glycerophosphorylcholine, guanidinoacetate, dimethylglycine, pipecolate, and phosphatidylserine. However, there were quite a few predictors which were unique to predicting cerebrovascular pathology, including 7‐hydroxycholesterol – common to atherosclerotic plaques, methylphosphate – an intermediate of purine and pyrimidine metabolism, 2‐methylcitrate/homocitrate – part of the TCA cycle, tryptophan – a precursor of serotonin and melatonin, 2‐hydroxystearate – a fatty acid, glutamate – the most abundant fast excitatory neurotransmitter, and beta‐hydroxyisovalerate – associated with smoking. Conclusion Many metabolites differed between the brains with cerebrovascular pathology and control brains. Some metabolite differences were the same as those seen in Alzheimer’s disease, and could be because many of the people in our cohort with cerebrovascular pathology also had Alzheimer’s pathology. Many of the metabolite differences were specific to cerebrovascular pathology including the well‐known lifestyle factors high cholesterol and smoking, and other metabolites which are critical to maintaining brain function, including changes in neurotransmitters, essential amino acids, fatty acids, TCA cycle intermediates, and nucleic acid intermediates. Further studies are needed to examine whether these metabolites are consistently altered in cerebrovascular disease.