Metabolite differences in TDP‐43 proteinopathy and control human brain tissue

• Published in: Alzheimer's & dementia Vol. 16
• Main Authors: Hammond, Tyler C., Xing, Xin, Nelson, Peter T., Ham, Stephanie, Lin, Ai‐Ling
• Format: Journal Article
• Language: English
• Published: 01.12.2020
• ISSN: 1552-5260; 1552-5279
• DOI: 10.1002/alz.044199

Background Limbic‐predominant age‐related TDP‐43 encephalopathy (LATE) is a newly recognized neurodegenerative disease that presents as an amnestic dementia syndrome that mimics Alzheimer’s‐type dementia. The hallmark neurodegenerative feature of LATE is a TDP‐43 proteinopathy distributed throughout the frontotemporal lobe. The main neuropathological and clinical features for LATE have been described elsewhere, but little is understood about the underlying metabolic processes that may contribute to TDP‐43 pathology in LATE. Here we measure the metabolites of control brains and brains with TDP‐43 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 44 subjects with TDP‐43 proteinopathy and 29 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 TDP‐43 presence in tissue. Result There were many metabolites that differed between TDP‐43 and control brains. Many of the metabolites in the top 20 most important predictors overlapped with metabolites deemed important in predicting Alzheimer’s disease, including memantine, sphingadienine, 3‐ureidopropionate, pyridoxal phosphate, 2’‐AMP, 3’‐AMP, pipecolate, 1‐carboxyethylvaline, sphingosine, and malate. However, there were quite a few predictors which were unique to predicting TDP‐43 proteinopathy, including tryptophan – a precursor of serotonin and melatonin, tetradecadienoate – a fatty acid, dihydroxyacetone phosphate (DHAP) – a glycolysis intermediate, homocarnosine – an intermediate in histidine metabolism that can co‐exist with progressive mental deficiency, and phosphatidylcholine and sphingomyelin – important components of the cell membrane. Conclusion Many metabolites differed between the TDP‐43 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 TDP‐43 pathology also had Alzheimer’s pathology. Many of the metabolite differences were specific to TDP‐43 proteinopathy, which are critical to maintaining brain function, including changes in neurotransmitters, essential amino acids, fatty acids, glycolysis intermediates, and cell membrane products. Further studies are needed to examine whether these metabolites are consistently altered in TDP‐43 proteinopathy.