Non-Targeted Metabolomics Approach Revealed Significant Changes in Metabolic Pathways in Patients with Chronic Traumatic Encephalopathy

Abstract

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease that is frequently found in athletes and those who have experienced repetitive head traumas. CTE is associated with a variety of neuropathologies, which cause cognitive and behavioral impairments in CTE patients. However, currently, CTE can only be diagnosed after death via brain autopsy, and it is challenging to distinguish it from other neurodegenerative diseases with similar clinical features. To better understand this multifaceted disease and identify metabolic differences in the postmortem brain tissues of CTE patients and control subjects, we performed ultra-high performance liquid chromatography–mass spectrometry (UPLC-MS)-based non-targeted metabolomics. Through multivariate and pathway analysis, we found that the brains of CTE patients had significant changes in the metabolites involved in astrocyte activation, phenylalanine, and tyrosine metabolism. The unique metabolic characteristics of CTE identified in this study were associated with cognitive dysfunction, amyloid-beta deposition, and neuroinflammation. Altogether, this study provided new insights into the pathogenesis of CTE and suggested appealing targets for both diagnosis and treatment for the disease.

Advances Research in Traumatic Encephalopathy

“…Clearly, the pathophysiologic differences between CTE and other neurodegenerative diseases such as AD are not well appreciated. To this end, one study in this special edition seeks to uncover unique metabolic pathways in the pathophysiology of CTE [ 25 ]. In this study, samples from the temporal lobes of 10 CTE 9 normal postmortem human brains were analyzed using three methods: (1) separation and quantification of metabolites with high-performance liquid chromatography (HPLC), (2) RNA sequencing, and (3) the direct immunohistochemistry of the samples.…”

“…One important finding in this work was the alteration in aromatic amino acid (phenylalanine, tyrosine, and tryptophan) metabolism [ 25 ]. Following previous findings revealing that aromatic amino acids may play a neuroprotective role in reducing intracranial pressure following injury [ 26 ], their dysregulated metabolism in CTE may present a new mechanism of CTE progression.…”

“…Interestingly, though reductions in COMT and MAOA activity are associated with behavioral aggression very similar to that seen in CTE patients [ 28 , 29 ], the RNA expression of the catecholamine degradation enzymes COMT and MAOA were elevated in this study. However, elevations in this metabolic pathway may contribute to p-tau accumulation and disease progression [ 25 ]. Taken together, these results shed light on the pathologic alterations to metabolic pathways in CTE.…”