Cargando…

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

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 encephalopath...

Descripción completa

Detalles Bibliográficos
Autores principales: Scholefield, Melissa, Church, Stephanie J., Xu, Jingshu, Patassini, Stefano, Roncaroli, Federico, Hooper, Nigel M., Unwin, Richard D., Cooper, Garth J. S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8571017/
https://www.ncbi.nlm.nih.gov/pubmed/34751215
http://dx.doi.org/10.3389/fnmol.2021.711396
_version_ 1784594935475863552
author Scholefield, Melissa
Church, Stephanie J.
Xu, Jingshu
Patassini, Stefano
Roncaroli, Federico
Hooper, Nigel M.
Unwin, Richard D.
Cooper, Garth J. S.
author_facet Scholefield, Melissa
Church, Stephanie J.
Xu, Jingshu
Patassini, Stefano
Roncaroli, Federico
Hooper, Nigel M.
Unwin, Richard D.
Cooper, Garth J. S.
author_sort Scholefield, Melissa
collection PubMed
description 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.
format Online
Article
Text
id pubmed-8571017
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher Frontiers Media S.A.
record_format MEDLINE/PubMed
spelling pubmed-85710172021-11-07 Severe and Regionally Widespread Increases in Tissue Urea in the Human Brain Represent a Novel Finding of Pathogenic Potential in Parkinson’s Disease Dementia Scholefield, Melissa Church, Stephanie J. Xu, Jingshu Patassini, Stefano Roncaroli, Federico Hooper, Nigel M. Unwin, Richard D. Cooper, Garth J. S. Front Mol Neurosci Neuroscience 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. Frontiers Media S.A. 2021-10-22 /pmc/articles/PMC8571017/ /pubmed/34751215 http://dx.doi.org/10.3389/fnmol.2021.711396 Text en Copyright © 2021 Scholefield, Church, Xu, Patassini, Roncaroli, Hooper, Unwin and Cooper. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Neuroscience
Scholefield, Melissa
Church, Stephanie J.
Xu, Jingshu
Patassini, Stefano
Roncaroli, Federico
Hooper, Nigel M.
Unwin, Richard D.
Cooper, Garth J. S.
Severe and Regionally Widespread Increases in Tissue Urea in the Human Brain Represent a Novel Finding of Pathogenic Potential in Parkinson’s Disease Dementia
title Severe and Regionally Widespread Increases in Tissue Urea in the Human Brain Represent a Novel Finding of Pathogenic Potential in Parkinson’s Disease Dementia
title_full Severe and Regionally Widespread Increases in Tissue Urea in the Human Brain Represent a Novel Finding of Pathogenic Potential in Parkinson’s Disease Dementia
title_fullStr Severe and Regionally Widespread Increases in Tissue Urea in the Human Brain Represent a Novel Finding of Pathogenic Potential in Parkinson’s Disease Dementia
title_full_unstemmed Severe and Regionally Widespread Increases in Tissue Urea in the Human Brain Represent a Novel Finding of Pathogenic Potential in Parkinson’s Disease Dementia
title_short Severe and Regionally Widespread Increases in Tissue Urea in the Human Brain Represent a Novel Finding of Pathogenic Potential in Parkinson’s Disease Dementia
title_sort severe and regionally widespread increases in tissue urea in the human brain represent a novel finding of pathogenic potential in parkinson’s disease dementia
topic Neuroscience
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8571017/
https://www.ncbi.nlm.nih.gov/pubmed/34751215
http://dx.doi.org/10.3389/fnmol.2021.711396
work_keys_str_mv AT scholefieldmelissa severeandregionallywidespreadincreasesintissueureainthehumanbrainrepresentanovelfindingofpathogenicpotentialinparkinsonsdiseasedementia
AT churchstephaniej severeandregionallywidespreadincreasesintissueureainthehumanbrainrepresentanovelfindingofpathogenicpotentialinparkinsonsdiseasedementia
AT xujingshu severeandregionallywidespreadincreasesintissueureainthehumanbrainrepresentanovelfindingofpathogenicpotentialinparkinsonsdiseasedementia
AT patassinistefano severeandregionallywidespreadincreasesintissueureainthehumanbrainrepresentanovelfindingofpathogenicpotentialinparkinsonsdiseasedementia
AT roncarolifederico severeandregionallywidespreadincreasesintissueureainthehumanbrainrepresentanovelfindingofpathogenicpotentialinparkinsonsdiseasedementia
AT hoopernigelm severeandregionallywidespreadincreasesintissueureainthehumanbrainrepresentanovelfindingofpathogenicpotentialinparkinsonsdiseasedementia
AT unwinrichardd severeandregionallywidespreadincreasesintissueureainthehumanbrainrepresentanovelfindingofpathogenicpotentialinparkinsonsdiseasedementia
AT coopergarthjs severeandregionallywidespreadincreasesintissueureainthehumanbrainrepresentanovelfindingofpathogenicpotentialinparkinsonsdiseasedementia