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

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.

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“…Urea being a nitrogenous base of protein metabolism, its increase in the brains of PD patients has been subjected to much debate, especially in conditions where blood urea remained normal. The blood-brain barrier (BBB) is impermeable to urea; hence, increased brain urea levels in the present study indicate either increased synthesis of brain urea inside the central nervous system or breakage of BBB 54 . A similar experimental study on PD also suggests increased brain urea in Wistar rats induced with rotenone 37 .…”

Comparison of the biological effects of gadodiamide (Omniscan) and gadoteridol (ProHance) by means of multi-organ and plasma metabolomics

“…In recent years, diffused elevations in brain urea have been reported in certain types of age-related neurodegenerative diseases, i.e., Alzheimer's disease (AD), 53 Huntington's disease (HD) 54,55 and Parkinson disease (PD). 56 Urea cycle activity localizes primarily in the liver, but systemic over-production of urea is not known in AD and HD. These findings have been correlated to impaired local urea regulation in brain, by up-regulation of synthesis and/or defective clearance.…”

UPLC/Q-TOF MS-Based Urine Metabonomics Study to Identify Diffuse Axonal Injury Biomarkers in Rat

“…In this study, urea was significantly upregulated in urine samples from injury groups compared to the control group. Urea is substantial nitrogen- (N-) containing end product of protein metabolism, having a critical effect on excreting dangerous N-containing substances [ 19 , 20 ]. Ammonia will be transformed into urea during the urea cycle, while urea is later discharged through urine out of the body [ 19 ].…”

“…Moreover, the excess released glutamate is reduced through the urea cycle and shortens the tricarboxylic acid cycle-induced glutamate oxidation [ 24 ]. Furthermore, previous research showed that brain urea played a pivotal role in neurodegenerative diseases and was significantly increased in Parkinson's disease dementia (PDD), Huntington's disease (HD), and Alzheimer's disease (AD) [ 20 ]. During DAI, the upregulated urea in urine could be an endogenous protective mechanism to reduce subsequent axonal damage postinjury.…”