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Severe and Regionally Widespread Increases in Tissue Urea in the Human Brain Represent a Novel Finding of Pathogenic Potential in Parkinson’s Disease Dementia

Authors :
Melissa Scholefield
Stephanie J. Church
Jingshu Xu
Stefano Patassini
Federico Roncaroli
Nigel M. Hooper
Richard D. Unwin
Garth J. S. Cooper
Source :
Frontiers in Molecular Neuroscience, Vol 14 (2021)
Publication Year :
2021
Publisher :
Frontiers Media S.A., 2021.

Abstract

Widespread elevations in brain urea have, in recent years, been reported in certain types of age-related dementia, notably Alzheimer’s disease (AD) and Huntington’s disease (HD). Urea increases in these diseases are substantive, and approximate in magnitude to levels present in uraemic encephalopathy. In AD and HD, elevated urea levels are widespread, and not only in regions heavily affected by neurodegeneration. However, measurements of brain urea have not hitherto been reported in Parkinson’s disease dementia (PDD), a condition which shares neuropathological and symptomatic overlap with both AD and HD. Here we report measurements of tissue urea from nine neuropathologically confirmed regions of the brain in PDD and post-mortem delay (PMD)-matched controls, in regions including the cerebellum, motor cortex (MCX), sensory cortex, hippocampus (HP), substantia nigra (SN), middle temporal gyrus (MTG), medulla oblongata (MED), cingulate gyrus, and pons, by applying ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). Urea concentrations were found to be substantively elevated in all nine regions, with average increases of 3–4-fold. Urea concentrations were remarkably consistent across regions in both cases and controls, with no clear distinction between regions heavily affected or less severely affected by neuronal loss in PDD. These urea elevations mirror those found in uraemic encephalopathy, where equivalent levels are generally considered to be pathogenic, and those previously reported in AD and HD. Increased urea is a widespread metabolic perturbation in brain metabolism common to PDD, AD, and HD, at levels equal to those seen in uremic encephalopathy. This presents a novel pathogenic mechanism in PDD, which is shared with two other neurodegenerative diseases.

Details

Language :
English
ISSN :
16625099
Volume :
14
Database :
Directory of Open Access Journals
Journal :
Frontiers in Molecular Neuroscience
Publication Type :
Academic Journal
Accession number :
edsdoj.19001ef99efe4d14957c087415473dbc
Document Type :
article
Full Text :
https://doi.org/10.3389/fnmol.2021.711396