UC Davis

Evaluating the effects of postmortem ischemia on brain metabolites has been a longstanding challenge in ex vivo metabolomic studies. This thesis sought to first evaluate which metabolites are affected by short-term postmortem ischemia in rats, through the use of head-focused microwave irradiation as a control group to one group receiving CO2-induced hypercapnia/ischemia with microwave irradiation, one group receiving CO2 and microwave irradiation with a postmortem interval simulating a typical dissection time, and one group receiving CO2 only (Study 1). The subsequent objective was to take the postmortem interval into account in an evaluation of metabolites in postmortem prefrontal cortex taken from AD patients and control patients, both with and without a cerebrovascular disease (CeVD) diagnosis (Study 2). CeVD represents a state of chronic ischemia potentially discernable from acute postmortem ischemia, which could manifest in metabolomic differences between AD and CeVD. Study 1 demonstrated substantial postmortem changes in brain energy and glycosylation pathways, as well as levels of amino acids, nucleotides, neurotransmitters, lipids, and antioxidants as a result of both ischemia and brain dissection, compared to controls subjected to head-focused microwave irradiation. Study 2 found that compared to controls without CeVD, AD patients without CeVD had reduced levels of fumarate, glutathione, and sarcosine, while α-hydroxybutyrate was confounded by age and postmortem interval in AD subjects without CeVD. This thesis demonstrates that postmortem ischemia should be considered as an important variable in postmortem brain metabolomic studies, to better determine metabolite changes that are potentially masked by the postmortem interval, especially with co-occurring vascular disease pathologies.